leptin and Prostatic-Neoplasms

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

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Obesity is associated with an increased risk of advanced, recurrent and fatal prostate cancer. Adipokines may mediate this relationship. We conducted a systematic review and meta-analysis of associations of leptin and adiponectin with overall and aggressive prostate cancer. Bibliographic databases were systematically searched up to 1st April 2017. Log Odds Ratios (ORs) per 2.5 unit increase in adiponectin or leptin levels were derived and pooled. All analyses were stratified by study type (cross-sectional/prospective). 746 papers were retrieved, 34 eligible studies identified, 31 of these could be included in the meta-analysis. Leptin was not consistently associated with overall prostate cancer (pooled OR 1.00, 95%CI 0.98-1.02, per 2.5 ng/ml increase, prospective study OR 0.97, 95%CI 0.95-0.99, cross-sectional study OR 1.19, 95%CI 1.13-1.26) and there was weak evidence of a positive association with aggressive disease (OR 1.03, 95%CI 1.00-1.06). There was also weak evidence of a small inverse association of adiponectin with overall prostate cancer (OR 0.96, 95%CI 0.93-0.99, per 2.5 µg/ml increase), but less evidence of an association with aggressive disease (OR 0.98, 95%CI 0.94-1.01). The magnitude of any effects are small, therefore levels of circulating adiponectin or leptin alone are unlikely to be useful biomarkers of risk or prognosis.

Topics: Adiponectin; Humans; Leptin; Male; Prostatic Neoplasms; Risk

Obesity has been proposed as a risk factor for prostate cancer (PCa). In obesity, serum levels of the appetite-regulating hormones-leptin, adiponectin, and ghrelin-become deregulated.. To explore whether serum levels of appetite-regulating hormones associate with the incidence of PCa, the incidence of advanced disease, or PCa-specific mortality.. PRISMA guidelines were followed. A systematic search for relevant articles published until March 2019 was performed using the databases PubMed, EMBASE, and Web of Science. Observational studies with data on serum levels of leptin, adiponectin, or ghrelin and PCa outcome were included. Meta-analysis was used to combine risk estimates. Meta-relative risks (mRRs) were calculated using random effects models. When available, raw data was pooled. Publication bias was assessed by funnel plot and Begg's test.. Thirty-five studies were eligible for inclusion. The qualitative analysis indicated that leptin was not consistently associated with any PCa outcome, although several cohorts reported decreased adiponectin levels in men who later developed advanced PCa. Based on the meta-analysis, there was no significant effect of leptin on PCa incidence (mRR = 0.93 (95% CI 0.75-1.16), p = 0.52) or advanced PCa (mRR = 0.90 (95% CI 0.74-1.10), p = 0.30). There were insufficient studies to estimate the mRR of PCa incidence for men with the highest levels of adiponectin. The combined risk of advanced PCa for men with the highest levels of adiponectin was reduced but did not reach significance (mRR = 0.81 (95% CI 0.61-1.08), p = 0.15).. The current evidence does not suggest an association between leptin and PCa outcome. However, there may be an inverse association between adiponectin and the incidence of advanced PCa that should be investigated by further studies. Serum ghrelin has not been largely investigated.

Topics: Adiponectin; Appetite; Disease Susceptibility; Epithelial Cells; Gene Expression Regulation; Ghrelin; Humans; Leptin; Male; Obesity; Peptide Hormones; Prostatic Neoplasms; Publication Bias; Signal Transduction

The human prostate gland is an endocrine organ where dysregulation of various hormonal factors may play a pivotal role in the pathogenesis of prostate cancer. There is emerging epidemiological data to support the role of components of metabolic syndrome, namely, obesity, hypercholesterolaemia, diabetes and hyperinsulinaemia on the development and/or the progression of prostate cancer. Although the exact mechanisms behind the relationship between metabolic syndrome and prostate cancer remain largely unknown, various in vitro and animal experiments of metabolic syndrome models have been shown to promote survival, mitogenesis, metastasis and treatment resistance pathways, through various adaptive responses such as intracellular steroidogenesis and lipogenesis. Also, in a large proportion of men with metabolic syndrome, alteration in levels of hormones such as testosterone, leptin and adiponectin has been shown to contribute towards the aggression of prostate cancer. Whilst the exact bio-pathophysiological mechanisms between metabolic syndrome and prostate cancer are yet to be fully elucidated, medications that target specific components of metabolic syndrome have further provided evidence for the inter-relationship between metabolic syndrome, its components and prostate cancer. Emerging in vitro and molecular data is likely to bring us closer to utilizing this knowledge to target particular cancer survival pathways and improving outcomes for men with prostate cancer.

Topics: Adiponectin; Animals; Disease Progression; Genetic Predisposition to Disease; Humans; Leptin; Male; Metabolic Syndrome; Prostatic Neoplasms; Testosterone

Leptin and adiponectin signaling was associated with development and progression of various cancers. The present study aimed to clarify the role of genetic variants in leptin, adiponectin and their receptors in prostate cancer. After comprehensive search and manuscript scanning, a total of 49 genetic variants were enrolled and examined for their relations to cancer risk and aggressiveness. In the meta-analysis, LEP rs7799039 (allele contrast: OR 1.133, 95%CI 1.024-1.254), ADIPOQ rs2241766 (allele contrast: OR 1.201, 95%CI 1.015-1.422) and ADIPOR1 rs10920531 (allele contrast: OR 1.184, 95%CI 1.075-1.305) variants were identified to be correlated with increased risk of prostate cancer. On the contrary, LEPR rs1137101 (allele contrast: OR 0.843, 95%CI 0.730-0.973) and ADIPOR1 rs2232853 (allele contrast: OR 0.638, 95%CI 0.535-0.760) variants were associated with decreased risk of prostate cancer. From the pooled-review, we additionally recognized eight variants associated with cancer risk and another eight variants associated with cancer aggressiveness, respectively. These observations indicated important roles of leptin, adiponectin and their receptors in the development and progression of prostate cancer. The identified polymorphisms might assist in developing better risk-assessment tools, as well as generating novel targeted therapies, especially for obese cancer patients with impaired leptin and adiponectin signaling.

Topics: Adiponectin; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Genetic Predisposition to Disease; Humans; Leptin; Male; Neoplasm Grading; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Receptors, Adiponectin; Receptors, Leptin; Risk Assessment; Risk Factors; Signal Transduction; Time Factors; Treatment Outcome

The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited.Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive.Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.

Topics: Adipose Tissue; Animals; Carcinogenesis; Genetic Predisposition to Disease; Humans; Janus Kinases; Leptin; Male; Obesity; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

The leptin (LEP) gene has been considered to be implicated in the development of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of LEP rs7799039 variant with colorectal and prostate cancer risk. Published literatures from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed or random effects model. A total of five studies (2,596 colorectal cancer cases and 3,240 controls) for association of LEP rs7799039 variant with colorectal cancer, and three studies (1,343 prostate cancer cases and 1,238 controls) for association with prostate cancer were included in the meta-analysis. For colorectal cancer, there was no significant association of LEP rs7799039 variant with this disease under homogeneous co-dominant model (OR = 0.88, 95 % CI = 0.75-1.02), heterogeneous co-dominant model (OR = 1.00, 95 % CI = 0.89-1.13) and dominant model (OR = 0.97, 95 % CI = 0.87-1.08); however, there was a marginal association under recessive model (OR = 0.87, 95 % CI = 0.76-0.99). For prostate cancer, there was significant association of LEP rs7799039 variant with this disease under homogeneous co-dominant model (OR = 1.33, 95 % CI = 1.06-1.67) and recessive model (OR = 1.26, 95 % CI = 1.05-1.51), but not under heterogeneous co-dominant model (OR = 1.24, 95 % CI = 0.87-1.77) and dominant model (OR = 1.30, 95 % CI = 1.84). The present meta-analysis demonstrated that the LEP rs7799039 variant was associated with prostate cancer, but not with colorectal cancer.

Topics: Case-Control Studies; Colorectal Neoplasms; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leptin; Male; Odds Ratio; Polymorphism, Single Nucleotide; Prostatic Neoplasms

Numerous epidemiological studies have examined associations of genetic variations in LEP (G2548A, -2548 nucleotide upstream of the ATG start site) and LEPR (Q223R, nonsynonymous SNP in exon 6) with cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate such associations.. We searched published literature from MEDLINE, EMBASE, Web of Science and CBM for eligible publications. We also assessed genotype-based mRNA expression data from HapMap for rs7799039 (G2548A) and rs1137101 (Q223R) in normal cell lines derived from 270 subjects with different ethnicities.. The final analysis included 16 published studies of 6569 cases and 8405 controls for the LEP G2548A and 19 studies of 7504 cases and 9581 controls for the LEPR Q223R. Overall, LEP G2548A was statistically significantly associated with an increased risk of overall cancer (AA vs. GG: OR=1.27, 95% CI=1.05-1.54; recessive model: OR=1.19, 95% CI=1.00-1.41). Further stratifications by cancer type showed an increased risk for prostate cancer (recessive model: OR=1.26, 95% CI=1.05-1.51) but not for other cancers. For LEPR Q223R, no statistical evidence for an association with risk of cancer was found for all; however, further stratification by ethnicity showed an increased risk for Africans but not for other ethnicities. No significantly differences in LEP and LEPR mRNA expression were found among genotypes or by ethnicity.. Despite some limitations, this meta-analysis found some statistical evidence for an association between the LEP 2548AA genotype and overall risk of cancer, particularly for prostate cancer, but given this variant did not have an effect on mRNA expression, this association warrants additional validation in large and well-designed studies.

Topics: Case-Control Studies; Databases, Bibliographic; Genetic Predisposition to Disease; HapMap Project; Humans; Leptin; Male; Models, Genetic; Neoplasms; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Racial Groups; Receptors, Leptin; RNA, Messenger

There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.

Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Colorectal Neoplasms; Endometrial Neoplasms; Esophageal Neoplasms; Female; Humans; Kidney Neoplasms; Leptin; Male; Neoplasms; Obesity; Pancreatic Neoplasms; Prostatic Neoplasms; Thyroid Neoplasms

Many studies have investigated the association between obesity, adipose tissue-derived factors (leptin and adiponectin) and prostate cancer (CaP) but the results are still inconsistent.. The aim of this study was to carry out a comprehensive review of the existing evidence about the role of leptin and adiponectin in prostate carcinogenesis and to provide an overview of it.. Recent evidence suggests that leptin may play a rol in prostate cancer progression, while adiponectin may act as an "antiprostatic cancer" adipokine.. Obesity may promote the progression of established prostate cancer and and adipokines may provide a molecular mechanism whereby obesity exerts its effects on prostate tumour biology.

Topics: Adiponectin; Humans; Leptin; Male; Prostatic Neoplasms

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Topics: Animals; Atherosclerosis; Bone Density; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Hematocrit; Humans; Hypogonadism; Inflammation Mediators; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Prostatic Neoplasms; Sexual Dysfunction, Physiological; Testosterone

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer deaths among men in most Western countries. Despite its high morbidity and mortality, the etiology of prostate cancer remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data, including serological and genetic studies, are inconclusive. In this chapter, we review the status of serologic studies and discuss the importance of intra-prostatic hormone levels in possibly clarifying the often-contradictory data on serologic studies. To provide insights and directions for epidemiologic research on hormones and prostate cancer, this review centers on the molecular epidemiology of hormone-related genetic loci. These loci have been investigated in a number of studies to date and will undoubtedly expand even further as rich new genetic information sources and high-throughput genotyping and analysis methods become available. Due to the enormous number of these loci, we recommend careful analysis and cautious interpretation of studies of genetic markers, including microsatellites and single nucleotide polymorphisms (SNPs), as false positive and negative results are likely due to limited statistical power, multiple hypothesis testing, population stratification, or non-representative population sampling. This review also highlights the need for replication in various populations, as well as reasons for performing functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for concerted, large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.

Topics: Androgens; Estrogens; Gonadotropins; Humans; Insulin; Leptin; Male; Molecular Epidemiology; Prostatic Neoplasms; Receptors, Estrogen; Sex Hormone-Binding Globulin; Somatomedins; Vitamin D

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.

Topics: Abdominal Fat; Body Mass Index; Humans; Inflammation; Leptin; Male; Metabolic Syndrome; Obesity; Prostatic Neoplasms; Risk Factors; Somatomedins

Adipose tissue-produced hormones significantly affect the metabolism of lipids and carbohydrates as well as numerous other processes in human body. It is generally accepted that endocrine dysfunction of adipose tissue may represent one of the causal links between obesity and insulin resistance/diabetes. Epidemiological studies underlined that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined. Multiple recent studies have indicated that some of adipose tissue-derived hormones may significantly influence the growth and proliferation of tumorous stroma and malignant cells within. Here we review current knowledge about possible relationship of leptin and adiponectin to the etiopathogenesis of different malignant tumors. Most of the studies indicated that while leptin may potentiate the growth of cancer cells in vitro, adiponectin appears to have an opposite effect. Further studies are necessary to decide whether obesity-induced endocrine dysfunction of adipose tissue can directly influence carcinogenesis in different tissues and organs.

Topics: Adiponectin; Adipose Tissue; Breast Neoplasms; Female; Humans; Leptin; Male; Neoplasms; Prostatic Neoplasms

Obesity-associated prostate cancer (PCa) remains controversial, although most studies rely on body mass index evaluation, which is an indirect measure of fatness. Studies using body fat measurement and disease stratification according to PCa stage found stronger associations between obesity and PCa. Leptin is a pleiotrophic hormone mainly synthesized by adipocytes that acts in peripheral organs such as the prostate. This article reviews obesity-associated leptin's pathophysiological role in PCa progression. PCa development results from some known risk factors. Currently, there is enough evidence suggesting that leptin is an additional factor involved in advanced PCa occurrence, and obesity association with high-grade disease. Life-long exposure to genetic and/or environmental susceptibility factors that predispose to obesity and higher leptin levels may increase the risk for advanced PCa.

Topics: Chemoprevention; Humans; Leptin; Male; Obesity; Prostatic Neoplasms; Signal Transduction

Prostate cancer, the third most common cancer in men worldwide, varies substantially according to geographic region and race/ethnicity. Obesity and associated endocrine variation are foremost among the risk factors that may underlie these regional and ethnic differences. The association between obesity and prostate cancer incidence is complex and has yielded inconsistent results. Studies that have linked obesity with prostate cancer mortality, advanced stage disease, and higher grade Gleason score, however, have produced more consistent findings, indicating that obesity may not necessarily increase the risk of prostate cancer, but may promote it once established. Additionally, metabolic syndrome, which includes disturbed glucose metabolism and insulin bioactivity, may also be associated with prostate carcinogenesis. Adipokines, defined as biologically active polypeptides produced by adipose tissue, have been linked with a number of carcinogenic mechanisms, including angiogenesis, cell proliferation, metastasis, and alterations in sex-steroid hormone levels. A number of emerging studies have implicated the role of adipokines in prostate carcinogenesis. This review explores the specific roles of several adipokines as putative mediating factors between obesity and prostate cancer with particular attention to leptin, interleukin-6 (IL-6), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF) and adiponectin.

Topics: Adipose Tissue; Epidermal Growth Factor; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Obesity; Prostatic Neoplasms; Risk Factors; Vascular Endothelial Growth Factor A

This review examines the relationship between obesity and prostate cancer, with an update of recent research in this field.. A recent report of the Cancer Prevention Study II showed a direct relationship between increasing body mass index and prostate cancer mortality. However, the US Health Professionals Followup Study reported an inverse association between obesity and the risk of developing prostate cancer in men under 60 years of age or in those with a family history of prostate cancer. These studies illustrate the contradictory evidence linking obesity to prostate cancer risk and mortality. Body mass does not appear to affect the performance of prostate-specific antigen as a diagnostic test, and on prostate biopsy a lower body mass is associated with a higher cancer detection rate and a higher cancer volume as measured by core length involvement. In two recent radical prostatectomy series, obesity was associated with worse pathological features and higher biochemical recurrence rates. The higher risk of recurrence persisted in patients with organ-confined disease and negative surgical margins, implying that this risk is not related to surgical technique. Several potential biological mechanisms have been proposed to explain this link including hormonal alterations, hyperinsulinemia, glucose intolerance, and elevated insulin-like growth factor and leptin levels.. Recent literature provides evidence that obesity may promote the development of a more aggressive form of prostate cancer, resulting in higher recurrence rates after primary therapy and higher cancer mortality rates overall. The mechanism to explain the association between obesity and prostate cancer is unclear.

Topics: Body Mass Index; Comorbidity; Humans; Insulin Resistance; Leptin; Male; Neoplasm Recurrence, Local; Obesity; Prostatectomy; Prostatic Neoplasms; Risk Assessment

In an era of rapidly increasing prevalence of human obesity and associated health problems, leptin gene polymorphisms have drawn much attention in biomedical research. Leptin gene polymorphisms have furthermore drawn much attention from animal scientists for their possible roles in economically important production and reproduction traits. Of the polymorphisms reported for exonic, intronic, and promoter regions of the leptin gene, 16 have been included in association studies in humans, 19 in cattle, and 6 (all exonic or intronic) in pigs. In humans, associations have been found with overweight or (early-onset) obesity, non-insulin-dependent diabetes mellitus, prostate cancer, and non-Hodgkin's lymphoma. In cattle, associations have been found with feed intake, milk yield traits, carcass traits, and reproduction-related traits, and in pigs with feed intake, average daily gain, carcass traits (backfat/leanness), and reproduction performance traits. Many of the polymorphisms were only included in a limited number of association studies, or the phenotypes studied varied largely for a given polymorphism between studies. Therefore, many of the associations found for these polymorphisms need to be confirmed in future studies before firm conclusions can be drawn.

Topics: Animals; Cattle; Diabetes Mellitus, Type 2; DNA, Complementary; Exons; Humans; Introns; Leptin; Lymphoma, Non-Hodgkin; Male; Obesity; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Prostatic Neoplasms; Swine

Topics: Adipocytes; Animals; Anorexia; Breast Neoplasms; Cell Differentiation; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Growth Substances; Humans; Leptin; Leukemia; Male; Neoplasms; Prostatic Neoplasms

Leptin's relation with obesity has been clearly demonstrated while its role in oncobiology is still largely unknown. Epidemiological studies on serum leptin provide valuable though controversial data, while in vitro studies consistently show leptin's angiogenic and proliferative potential in cancer. Leptin's activity is mediated by tissue-specific receptors, differentially expressed in organs such as the prostate. The molecular cascades triggered by leptin result in prostatic cell proliferation and angiogenic activity, thus linking the hormone mainly to prostate cancer prognosis. This review also addresses leptin's metabolic interactions with cytokines, growth factors or hormones, establishing perceptive pathways leading to carcinogenesis or prostate cancer progression and metastasis. Better understanding of these mechanisms may help in the development of new and more effective treatments for prostate cancer. The consolidation of leptin molecular genetics profile in prostate cancer patients may help to create susceptibility groups in normal individuals, facilitating a preventive dietary intervention or strategies for chemoprevention. We hypothesize that the balance between androgen and leptin levels may facilitate the increase in the ratio of androgen-independent prostate cancer cells to androgen-dependent cells in the tumour.

Topics: Cell Transformation, Neoplastic; Chemoprevention; Diet; Genetic Predisposition to Disease; Humans; Leptin; Male; Obesity; Prostatic Neoplasms; Risk Factors; Signal Transduction

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Obesity, metabolic syndrome, and hyperleptinemia are associated with aging and age-associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied plasma samples from men with prostate cancer awaiting prostatectomy who participated in a randomized trial of one month of PR or control diet. We found increased levels of leptin receptor in the PR group in total plasma EVs and in a subpopulation of plasma EVs expressing the neuronal marker L1CAM. Protein restriction also shifted the phosphorylation status of the insulin receptor signal transducer protein IRS1 in L1CAM+ EVs in a manner suggestive of improved insulin sensitivity. Dietary PR modifies indicators of leptin and insulin signaling in circulating EVs. These findings are consistent with improved insulin and leptin sensitivity in response to PR and open a new window for following physiologic responses to dietary interventions in humans.

Topics: Caloric Restriction; Diet, Protein-Restricted; Energy Metabolism; Extracellular Vesicles; Humans; Insulin; Leptin; Male; Middle Aged; Prostatic Neoplasms

Physical activity after prostate cancer diagnosis has been shown to reduce the risk of disease progression. Here, we aimed to evaluate the effect of a 2-year home-based endurance training intervention on body composition, biomarkers levels, and prostate-specific antigen (PSA) doubling time as a surrogate end-point for progressing disease.. Out-clinic patients with either biochemical recurrence following radical prostatectomy or patients managed on active surveillance were randomized to either 24 months (3 times/week) of home-based endurance training or usual care. Aerobic fitness, body composition, insulin sensitivity, and biomarkers were measured at 0, 6, and 24 months of intervention. PSA doubling time (PSADT) was calculated based on monthly PSA measurements.. Twenty-five patients were enrolled, and 19 patients completed the study. PSADT increased in the training group from 28 to 76 months (p < 0.05) during the first 6 months and was correlated with changes in VO2max (p < 0.01, r (2) = 0.41). The training group lost 3.6 ± 1.0 kg (p < 0.05) exclusively as fat mass, yet the changes in body composition were not associated with the increased PSADT. The training group showed significant improvements in plasma triglycerides, adiponectin, IGF-1, IGFBP-1, and fasting glucose levels, but no changes in insulin sensitivity (measured as Matsuda index), testosterone, cholesterols, fasting insulin, plasma TNF-alpha, IL-6, or leptin levels. The control group showed no changes in any of the evaluated parameters across the 2-year intervention.. In this small randomized controlled trial, we found that improvements in fitness levels correlated with increasing PSADT, suggesting a link between training and disease progression.

Topics: Adiponectin; Aged; Body Composition; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Disease Progression; Exercise Test; Exercise Therapy; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Middle Aged; Motor Activity; Neoplasm Recurrence, Local; Oxygen Consumption; Physical Endurance; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha

Experimental and prevalent case-control studies suggest an association between biomarkers of inflammation, endothelial function, and adiposity and cancer risk, but results from prospective studies have been limited. The authors' objective was to prospectively examine the relations between these biomarkers and cancer risk. A nested case-control study was designed within the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) Study, a nationwide French cohort study, to include all first primary incident cancers diagnosed between 1994 and 2007 (n = 512). Cases were matched with randomly selected controls (n = 1,024) on sex, age (in 2-year strata), body mass index (weight (kg)/height (m)(2); <25 vs. ≥25), and SU.VI.MAX intervention group. Conditional logistic regression was used to study the associations between prediagnostic levels of high-sensitivity C-reactive protein (hs-CRP), adiponectin, leptin, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble E-selectin, and monocyte chemoattractant protein 1 and cancer risk. All statistical tests were 2-sided. Plasma sICAM-1 level was positively associated with breast cancer risk (for quartile 4 vs. quartile 1, multivariate odds ratio (OR) = 1.86, 95% confidence interval (CI): 1.06, 3.26; P(trend) = 0.048). Plasma hs-CRP level was positively associated with prostate cancer risk (for quartile 4 vs. quartile 1, multivariate OR = 3.04, 95% CI: 1.28, 7.23; P(trend) = 0.03). These results suggest that prediagnostic hs-CRP and sICAM-1 levels are associated with increased prostate and breast cancer risk, respectively.

Topics: Adiponectin; Adiposity; Adult; Biomarkers; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Cell Adhesion Molecules; Chemokine CCL2; Double-Blind Method; Endothelium; Female; Health Behavior; Humans; Inflammation; Leptin; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Risk Factors

Recent studies indicate that adipose tissue and adipocytokines might affect the development of prostate cancer (PCa). Leptin would have a stimulating effect on prostate cancer cells by inducing promotion and progression, whereas adiponectin would have a protective effect. The aim of this study was to determine the relation between body composition, leptin, and adiponectin levels with the prevalence and aggressiveness of PCa in men of Mendoza, Argentina. Seventy volunteers between 50 and 80 years (35 healthy men as control group and 35 with PCa) were selected. The PCa group was subclassified according to the Gleason Score (GS). Digital rectal examination, transrectal ultrasound, and prostatic biopsy were performed; PSA, testosterone, leptin, and adiponectin levels were determined; and a nutritional interview including anthropometric measurements and a food frequency questionnaire was carried out. Statistical analysis was performed by Student t test, ANOVA I, and Bonferroni (p < 0.05). Body mass index and percentage of body fat mass were not statistically different between PCa and control groups. However, body fat mass was higher in subjects with more aggressive tumors (p = 0.032). No differences were observed regarding leptin levels between the groups. Nevertheless, leptin levels were higher in subjects with high GS (p < 0.001). Adiponectin levels showed no statistical differences regarding the presence and aggressiveness of the tumor (p = 0.131). Finally, consumption and nutrient intake did not differ in the studied groups. In conclusion, body composition and leptin are related to the PCa aggressiveness but not with its prevalence.

Topics: Adiponectin; Aged; Aged, 80 and over; Analysis of Variance; Body Mass Index; Humans; Leptin; Male; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Peptide Fragments; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Hyperinsulinemia and obesity-related metabolic disturbances are common and have been associated with increased cancer risk and poor prognosis. To investigate this issue in relation to prostate cancer, we conducted a nested case-control study within the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial testing finasteride versus placebo for primary prevention of prostate cancer. Cases (n = 1,803) and controls (n = 1,797) were matched on age, PCPT treatment arm, and family history of prostate cancer; controls included all eligible non-whites. Baseline bloods were assayed for serum C-peptide (marker of insulin secretion) and leptin (an adipokine) using ELISA. All outcomes were biopsy determined. Logistic regression calculated odds ratios (OR) for total prostate cancer and polytomous logistic regression calculated ORs for low-grade (Gleason <7) and high-grade (Gleason >7) disease. Results were stratified by PCPT treatment arm for C-peptide. For men on placebo, higher versus lower serum C-peptide was associated with a nearly 2-fold increased risk of high-grade prostate cancer (Gleason >7; multivariate-adjusted OR, 1.88; 95% confidence interval, 1.19-2.97; P(trend) = 0.004). When C-peptide was modeled as a continuous variable, every unit increase in log(C-peptide) resulted in a 39% increased risk of high-grade disease (P = 0.01). In contrast, there was no significant relationship between C-peptide and high-grade prostate cancer among men receiving finasteride. Leptin was not independently associated with high-grade prostate cancer. In conclusion, these results support findings from other observational studies that high serum C-peptide and insulin resistance, but not leptin, are associated with increased risk of high-grade prostate cancer. Our novel finding is that the C-peptide-associated risk was attenuated by use of finasteride.

Topics: C-Peptide; Case-Control Studies; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Finasteride; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Prostatic Neoplasms; Risk Factors

To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions.. The epidemiologic studies within SELECT will be based on 32,400 men aged 55 years or older (age 50 or older for the African-American men) enrolled into an intergroup, randomized, placebo-controlled, double-blind, phase III prevention trial of supplemental selenium and vitamin E developed and funded by the National Cancer Institute, and coordinated by the Southwest Oncology Group. During the 12-year study period approximately 1500-2000 cases of prostate cancer, 800 lung cancers, and 500 colon cancers are estimated to be diagnosed, based on data from the ongoing Prostate Cancer Prevention Trial of finasteride. A modified fasting blood sample will be processed to collect plasma for analysis of micronutrients, hormones, cytokines, and other proteins. Buffy-coat derived white blood cells collected at baseline will be used for isolation of DNA and establishment of immortalized cell lines. Red blood cells will be stored for analysis of hemoglobin adducts and other components.. Specific results anticipated from these molecular studies will provide information on factors hypothesized to contribute to prostate cancer risk and that may modify the efficacy of either trial supplement, including: steroid sex hormones and several polymorphic genes that encode proteins affecting androgenic stimulation of the prostate, including the androgen receptor, steroid 5alpha-reductase type II, CYP17, and beta-hydroxysteroid dehydrogenase; polymorphisms of DNA repair genes and carcinogen metabolism genes, including those involved in the activation of chemical carcinogens to reactive intermediates (e.g., CYP1A1) or the detoxification of reactive intermediates (e.g., glutathione S-transferase M1); DNA and protein adducts; and insulin-like growth factors and leptin.. SELECT offers an excellent opportunity to conduct molecular epidemiologic investigations to assess gene-environment interactions and their role in prostate, lung, and colon carcinogenesis.

Topics: Colorectal Neoplasms; Double-Blind Method; Epidemiologic Studies; Genetic Markers; Gonadal Steroid Hormones; Humans; Leptin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Risk Factors; Selenium; United States; Vitamin E

Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Dogs; Exons; Humans; Leptin; Lymphoma; Mice; Obesity; Prostatic Neoplasms; Tumor Protein p73

Sensitive and quantitative detection of molecular biomarkers is crucial for the early diagnosis of diseases like metabolic syndrome and cancer. Here we present a single-molecule sandwich immunoassay by imaging the number of single nanoparticles to diagnose aggressive prostate cancer. Our assay employed the photo-stable upconversion nanoparticles (UCNPs) as labels to detect the four types of circulating antigens in blood circulation, including glypican-1 (GPC-1), leptin, osteopontin (OPN), and vascular endothelial growth factor (VEGF), as their serum concentrations indicate aggressive prostate cancer. Under a wide-field microscope, a single UCNP doped with thousands of lanthanide ions can emit sufficiently bright anti-Stokes' luminescence to become quantitatively detectable. By counting every single streptavidin-functionalized UCNP which specifically labeled on each sandwich immune complex across multiple fields of views, we achieved the Limit of Detection (LOD) of 0.0123 ng/ml, 0.2711 ng/ml, 0.1238 ng/ml, and 0.0158 ng/ml for GPC-1, leptin, OPN and VEGF, respectively. The serum circulating level of GPC-1, leptin, OPN, and VEGF in a mixture of 10 healthy normal human serum was 25.17 ng/ml, 18.04 ng/ml, 11.34 ng/ml, and 1.55 ng/ml, which was within the assay dynamic detection range for each analyte. Moreover, a 20% increase of GPC-1 and OPN was observed by spiking the normal human serum with recombinant antigens to confirm the accuracy of the assay. We observed no cross-reactivity among the four biomarker analytes, which eliminates the false positives and enhances the detection accuracy. The developed single upconversion nanoparticle-assisted single-molecule assay suggests its potential in clinical usage for prostate cancer detection by monitoring tiny concentration differences in a panel of serum biomarkers.

Topics: Biomarkers; Humans; Leptin; Male; Nanoparticles; Prostatic Neoplasms; Vascular Endothelial Growth Factor A

MicroRNAs (miRNAs) are single-stranded non-coding RNA molecules that play a regulatory role in gene expression and cancer cell signaling. We previously identified miR-628-5p (miR-628) as a potential biomarker in serum samples from men with prostate cancer (PCa) (Srivastava et al. in Tumour Biol 35:4867-4873, 10.1007/s13277-014-1638-1, 2014). This study examined the detailed cellular phenotypes and pathways regulated by miR-628 in PCa cells. Since obesity is a significant risk factor for PCa, and there is a correlation between levels of the obesity-associated hormone leptin and PCa development, here we investigated the functional relationship between leptin and miR-628 regulation in PCa. We demonstrated that exposure to leptin downregulated the expression of miR-628 and increased cell proliferation/migration in PCa cells. We next studied the effects on cancer-related phenotypes in PCa cells after altering miR-628 expression levels. Enforced expression of miR-628 in PCa cells inhibited cell proliferation, reduced PCa cell survival/migration/invasion/spheroid formation, and decreased markers of cell stemness. Mechanistically, miR-628 binds with the JAG1-3'UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628 downregulated Notch signaling, decreased the expression of Snail/Slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, expression of miR-628 in PCa cells increased sensitivity towards the drugs enzalutamide and docetaxel by induction of cell apoptosis. Collectively our data suggest that miR-628 is a key regulator of PCa carcinogenesis and is modulated by leptin, offering a novel therapeutic opportunity to inhibit the growth of advanced PCa.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Jagged-1 Protein; Leptin; Male; MicroRNAs; Obesity; Prostatic Neoplasms

Metabolic syndrome (MetS) is a risk factor for prostate cancer (PCa) progression. Thus, this life-threatening disease demands a proactive treatment strategy. Andrographis paniculata (AP) is a promising candidate with various medicinal properties. However, the bioactivity of AP is influenced by its processing conditions especially the extraction solvent.. In the present study, bioassay-guided screening technique was employed to identify the best AP extract in the management of MetS, PCa, and MetS-PCa co-disease in vitro.. Five AP extracts by different solvent systems; APE1 (aqueous), APE2 (absolute methanol), APE3 (absolute ethanol), APE4 (40% methanol), and APE5 (60% ethanol) were screened through their phytochemical profile, in-vitro anti-cancer, anti-obese, and anti-hyperglycemic properties. The best extract was further tested for its potential in MetS-induced PCa progression.. In conclusion, AP extracts rich with andrographolide has the potential to be used as an alternative to ameliorate PCa progression induced by factors highly expressed in MetS.

Topics: Andrographis; Andrographis paniculata; Biological Assay; Diterpenes; Ethanol; Humans; Leptin; Male; Metabolic Syndrome; Methanol; Plant Extracts; Prostatic Neoplasms; Solvents

To better understand the link between obesity and prostate cancer (PC) aggressiveness, we investigate the role of leptin, an obesity associated adipokine, and its receptor (Ob-R) in PC cells migration. The migration assay (Wound-healing) was used to study the leptin impact on DU-145 and PC3 cells lines. STAT3 activation was performed by Western Blot. E-cadherin expression was studied using fluorescence microscopy and Ob-R expression in PC and benign prostatic Hyperplasia (BPH) biopsies was assessed by RT-PCR. In this study we demonstrate that high dose of leptin promotes PC cells migration and EMT transition via the stimulation of STAT3 pathway. In addition, we report that although Ob-R mRNA is expressed by ADK and BPH resections biopsies, significant higher levels were observed for ADK patients. Finally, we found a positive association between Ob-R mRNA expression and worse PC prognosis. A better understanding of the molecular processes of leptin signaling is crucial for identifying appropriate approaches for treatment of obesity-related PC patients.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Leptin; Male; Prostatic Neoplasms; Receptors, Leptin; STAT3 Transcription Factor

Excess fat mass (FM) contributes to poor prostate cancer (PCa) prognosis and comorbidity. However, FM gain is a common side effect of androgen deprivation therapy (ADT). We examined the efficacy of a 12-wk weight loss intervention to reduce FM and maintain lean mass (LM) in ADT-treated obese PCa patients.. Fourteen ADT-treated obese PCa patients (72 ± 9 yr, 39.7% ± 5.4% body fat) were recruited for a self-controlled prospective study, with 11 completing the 6-wk control period, followed by a 12-wk intervention comprising 300 min·wk-1 of exercise including supervised resistance training and home-based aerobic exercise, and dietitian consultations advising a daily energy deficit (2100-4200 kJ) and protein supplementation. Body composition was assessed by dual x-ray absorptiometry. Secondary outcomes included muscle strength (one-repetition maximum), cardiorespiratory fitness (maximal oxygen consumption), and blood biomarkers.. There were no significant changes during the control period. Patients attended 89% of supervised exercise sessions and 100% of dietitian consultations. No changes in physical activity or energy intake were observed. During the intervention, patients experienced significant reductions in weight (-2.8 ± 3.2 kg, P = 0.016), FM (-2.8 ± 2.6 kg, P < 0.001), and trunk FM (-1.8 ± 1.4 kg, P < 0.001), with LM preserved (-0.05 ± 1.6 kg, P = 0.805). Muscle strength (4.6%-24.7%, P < 0.010) and maximal oxygen consumption (3.5 ± 4.7 mL·min-1·kg-1, P = 0.041) significantly improved. Leptin significantly decreased (-2.2 (-2.7 to 0.5) ng·mL-1, P = 0.016) with no other changes in blood biomarkers such as testosterone and lipids (P = 0.051-0.765); however, C-reactive protein (rs = -0.670, P = 0.024) and triglycerides (r = -0.667, P = 0.025) were associated with individual changes in LM.. This study shows preliminary efficacy for an exercise and nutrition weight loss intervention to reduce FM, maintain LM, and improve muscle strength and cardiorespiratory fitness in ADT-treated obese PCa patients. The change in body composition may affect blood biomarkers associated with obesity and PCa progression; however, further research is required.

Topics: Absorptiometry, Photon; Adipose Tissue; Adiposity; Aged; Aged, 80 and over; Androgen Antagonists; Biomarkers; Cardiorespiratory Fitness; Energy Intake; Exercise; Humans; Leptin; Male; Middle Aged; Muscle Strength; Obesity; Oxygen Consumption; Prospective Studies; Prostatic Neoplasms; Resistance Training; Testosterone; Time Factors; Weight Loss

Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study, we uncover leptin as a novel universal target in PCa and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients' tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.

Topics: Androgen Antagonists; Androgens; Animals; Cell Line, Tumor; Heterografts; Humans; Leptin; Male; Mice; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Prostate cancer (PCa) is one of the most frequently diagnosed cancers worldwide. Despite the growing evidence associating obesity and adipokines, particularly leptin and its receptors, with cancer development and progression, it is still a debatable matter in PCa.. We aimed to assess the role of leptin and its receptors as potential biomarkers for the risk of PCa development and aggressiveness.. In this study, 176 men were included and categorized according to an established histopathological diagnosis into three age- and BMI-matched groups. The PCa group included 56 patients while the BPH group and the control group comprised 60 men each. Serum levels of total PSA (tPSA) were assessed by ELISA and mRNA expression levels of leptin and leptin receptors were assessed by RT-PCR.. Leptin and leptin receptor mRNA expression levels were significantly higher in PCa patients relative to BPH and to healthy control men. Both were overexpressed in PCa patients with aggressive and distantly metastasizing tumors compared to patients with confined tumors. Leptin receptor mRNA was an independent predictor of high Gleason score ≥ 7, distant metastasis, LN, and seminal vesicles invasion.. Leptin and its receptors are suggested to be potential biomarkers for PCa; leptin receptor mRNA might predict risk and aggressiveness of PCa.

Topics: Biomarkers, Tumor; Humans; Leptin; Male; Middle Aged; Prostatic Neoplasms; Receptors, Leptin; Risk Factors

The aim of this study was to investigate the effect of leptin (Lep) on the proliferation, invasion and apoptosis of prostate cancer cells through the extracellular regulated protein kinase 1/2 (ERK1/2) signaling pathway.. Prostate cancer DU145 cells in the logarithmic growth phase were randomly divided into Lep (10, 20, 40, 80, 160 and 320 ng/mL) groups and blank control (Con) group. After culture, the cells were treated for 6 h, 12 h and 24 h, respectively. The effects of Lep on the proliferation and invasion of DU145 cells were detected via methyl thiazolyl tetrazolium (MTT) assay and transwell chamber assay, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out to examine the messenger ribonucleic acid (mRNA) expressions of ERK1/2, b-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) in DU145 cells after Lep treatment for 24 h. Thereafter, immunofluorescence assay was performed to detect the localization of ERK1/2 protein in prostate cancer DU145 cells. In addition, the expressions of phosphorylated (p)-ERK, ERK1/2 and apoptosis-related proteins, Bcl-2, Bax and cleaved cysteinyl aspartate specific proteinase (c-Caspase 3) in prostate cancer DU145 cells after treatment with different concentrations of Lep for 24 h were examined by Western blotting.. MTT assay results showed that the proliferation rate of DU145 cells increased significantly at 6 h, 12 h and 24 h after 5-320 ng/mL of Lep treatment (p<0.05). Transwell assay manifested that the number of invasive cells was significantly raised after Lep treatment for 24 h (p<0.05). Meanwhile, the invasion ability of cells increased gradually with the elevation of Lep concentration. Subsequent qRT-PCR results demonstrated that after treatment with different concentrations of Lep, the mRNA expressions of ERK1/2 and Bcl-2 rose markedly (p<0.05). However, the mRNA expression of Bax was remarkably down-regulated (p<0.05) with the increase of Lep concentration in a concentration-dependent manner. According to the detection using a laser scanning confocal microscope, ERK1/2 red fluorescence showed punctiform aggregation, which was gradually raised with the increase of Lep concentration for 24 h. Moreover, Western blotting results denoted that with the increase of Lep concentration, the protein expressions of p-ERK, ERK1/2 and Bcl-2 were notably elevated (p<0.05), while those of Bax and c-Caspase 3 were distinctly reduced (p<0.05).. Lep activation induces the proliferation, promotes the invasion and inhibits the apoptosis of prostate cancer cells through the ERK1/2 signaling pathway.

Topics: Apoptosis; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Humans; Leptin; Male; Prostatic Neoplasms; Signal Transduction; Tumor Cells, Cultured

Leptin, the first discovered adipokine, has been connected to various physiological and pathophysiological processes, including cancerogenesis. Increasing evidence confirms its influence on prostate cancer cells. However, studies on the effects of leptin on the proliferation and apoptosis of the androgen-sensitive LNCaP line of prostate cancer cells brought conflicting results. Therefore, we performed studies on the effects of high LEP concentration (1 × 10

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Leptin; Male; Prostatic Neoplasms

Topics: Adipose Tissue; Age Factors; Aged; Body Mass Index; Correlation of Data; Dihydrotestosterone; Early Detection of Cancer; Estradiol; Humans; Leptin; Luteinizing Hormone; Male; Middle Aged; Neoplasm Grading; Obesity; Portugal; Prolactin; Prostatic Neoplasms; Risk Factors; Testosterone

Results of studies on the expression of leptin and its receptors in the human prostate gland and human prostate cell lines are contradictory. Regarding this, we carefully reinvestigated this issue using human normal prostate (PrEC, PrSC, PrSMC) and prostate cancer (DU145, LNCaP, PC3) cell lines. Expression of leptin receptor isoforms was assessed by qPCR while the effects of leptin on cell proliferative activity was determined by real-time cell analyzer (RTCA). Expression of the leptin receptor variant 1 was not detected in LNCaP and PrSMC cell lines, but it was found in the remaining cell lines. In contrast, in all examined cell lines, isoforms 1-3 and 2 and 4 of the leptin receptor were found. The expression of isoforms 3 and 6 of the leptin receptor was observed in PC3, PrEC, PrSMC and PrSC cell lines, but not in LNCaP and DU145 cells. Expression of the leptin receptor isoforms 4-6 and 5 was not demonstrated in any of the tested cell lines. We also studied the effects of leptin on the expression of its receptor isoforms in all tested cell lines. At a wide range of concentrations, leptin did not change the expression of leptin receptor variant 1 in the DU145, PrEC and PC3 cell lines. In contrast, in the PrSC cell line, leptin significantly increased the expression of this gene. In all prostate cell lines tested, leptin did not alter the expression levels of variants 1-3 of the leptin receptor isoforms. Leptin did not alter the expression of isoforms 2 and 4 of the leptin receptor in the PC3 and LNCaP cell lines. In the DU145 and PrEC cell lines, leptin inhibited expression of these receptor isoforms while an opposite effect was noted in the PrSC cells. Leptin did not affect the expression level of variants 3 and 6 of its receptor in the PrEC and PC3 cell lines. However, in PrSMC cells, leptin inhibited the expression of variants 3 and 6 of its receptor, while in the PrSC cell line this cytokine significantly increased their expression levels. As assessed by RTCA, leptin stimulated the proliferative activity of DU145 cells, but inhibited this activity in LNCaP cells. At all concentrations tested, leptin did not change the proliferation rate of the PC3, PrEC and PrSMC cells. In contrast, leptin notably stimulated the proliferative activity of the PrSC (prostate stromal cell) cell line. Thus, our study demonstrated that in all tested human normal prostate and prostate cancer cell lines, transcription variants 4, 5 and 6 of the leptin receptor were not expr

Topics: Cell Line; Cell Line, Tumor; Cell Proliferation; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Prostatic Neoplasms; Receptors, Leptin; RNA Isoforms

Obesity and prostate cancer are related, but the causal relationship remains unknown. The aim of the study was to compare concentrations of leptin, adiponectin and chemerin in patients with prostate cancer and benign prostate hyperplasia and to examine associations of the adipokines with the grade of prostate cancer, interleukin-6 (IL-6), insulin resistance and anthropometric and metabolic variables.. The study group consisted of 140 men divided into two groups: I- prostate cancer (n=74) and II- with benign hyperplasia (n=66). Serum leptin, adiponectin, chemerin, IL-6 and metabolic profile were measured. Considering histological differentiation prostate cancer patients were divided into 3 subgroups: well differentiated (Gleason score ≤ 6), moderately differentiated subgroup (Gleason 7), and poorly differentiated (Gleason ≥8).. There were no differences between groups in BMI, waist circumference, HOMA-I, serum levels of total cholesterol, glucose, triglycerides, adiponectin, leptin and chemerin. However, the concentrations of PSA, leptin-to-adiponectin ratio and IL-6 were significantly higher in cancer group compared with benign hyperplasia group. In the poorly differentiated cancer subgroup, subjects had higher PSA, leptin, chemerin, IL-6 and triglycerides concentrations. Overweight and obese men with prostate cancer were more likely to have moderately or poorly differentiated cancer than those with normal BMI. In the all men serum adiponectin was significantly correlated with HOMA-I, BMI, glucose, triglycerides, cHDL. There were significant correlations between leptin and BMI, HOMA-I, waist, glucose, triglycerides and cHDL. Among all the participants we observed associations between chemerin and waist as well as triglycerides. In prostate cancer patients chemerin correlated with IL-6 and leptin. We measured significant positive correlations between Gleason score and chemerin and leptin concentrations. There was a positive correlation between adiponectin and PSA levels in all men, as well as in cancer group.. Leptin-to-adiponectin ratio and IL-6 were elevated in men with prostate cancer. Leptin, chemerin and IL-6 were associated with Gleason score. The relationships between leptin, chemerin and IL-6 were dependent on each other. Overweight and obese men had a higher Gleason score.

Topics: Adipokines; Adiponectin; Aged; Chemokines; Humans; Hyperplasia; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Prostate; Prostatic Neoplasms

Adipose tissue-derived adipokines (i.e., leptin/adiponectin/resistin) play important roles in the regulation of several pathophysiologic processes through the activation of specific receptors. However, although adipokines and their receptors are widely distributed in many tissues and exhibit a clear modulation according to particular metabolic conditions (e.g., obesity and/or fasting), their expression, regulation, and putative action on normal prostate glands (PGs; a hormone-dependent organ tightly regulated by the endocrine-metabolic milieu) are still to be defined. Different in vivo/in vitro models were used to comprehensively characterize the expression pattern and actions of different adipokine systems (i.e., leptin/adiponectin/resistin/receptors) in mouse PGs. Adiponectin, resistin, and adiponectin receptors (1 and 2) and leptin receptor are coexpressed at different levels in PG cells, wherein they are finely regulated under fasting and/or obesity conditions. Furthermore, treatment with different adipokines exerted both homologous and heterologous regulation of specific adipokines/receptor-synthesis and altered the expression of key proliferation and oncogenesis markers (i.e., Ki67/c-Myc/p53) in mouse PG cell cultures, wherein some of these actions might be elicited through extracellular signal-regulated kinase (ERK) activation. Moreover, treatment with leptin, adiponectin, and resistin differentially regulated key functional parameters [i.e., proliferation and migration capacity and/or prostate-specific antigen (PSA) secretion] in human normal and/or tumoral prostate cell lines. Altogether, our data show that various adipokine and receptor systems are differentially expressed in normal PG cells; that their expression is under a complex ligand- and receptor-selective regulation under extreme metabolic conditions; and that they mediate distinctive and common direct actions in normal and tumoral PG cells (i.e., homologous and heterologous regulation of ligand and receptor synthesis, ERK signaling activation, modulation of proliferation markers, proliferation and migration capacity, and PSA secretion), suggesting a relevant role of these systems in the regulation of PG pathophysiology.

Topics: Adipokines; Adiponectin; Animals; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Fasting; Humans; Ki-67 Antigen; Leptin; Male; MAP Kinase Signaling System; Mice; Obesity; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-myc; Real-Time Polymerase Chain Reaction; Receptors, Adiponectin; Receptors, Leptin; Resistin; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Protein p53

To assess sex hormones, leptin and insulin-resistance in men with prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and to study associations between androgens and histologic score of prostate tissue in PCa.. Two hundred ten men older than 45 years selected from 2906 participants of a population screening for PCa were studied: 70 with PCa, 70 with BPH and 70 controls (CG), matched by body mass index and age. Insulin, IGF-1, PSA, leptin, total, free (fT) and bioavailable testosterone (bT) and estradiol were measured. Each group was subdivided into two subgroups considering the presence of metabolic syndrome (MS); androgens and leptin levels were analyzed in the subgroups.. Prostate cancer and BPH patients presented higher total, fT and bT levels than CG. IGF-1, insulin and HOMA index were higher in BPH than in the other two groups. PCa presented higher leptin [median (range) 6.5 (1.3-28.0) versus 4.8 (1.1-12.3) ng/ml; p < 0.01] and estradiol [median (range) 37.0 (20-90) versus 29.0 (20-118) pg/ml; p = 0.025] levels than CG. After dividing men considering the presence of MS, leptin was higher and total testosterone was lower in MS patients in all the groups.. It was observed a coexistence of an altered hormone profile with increased sex hormones and leptin in PCa patients, in accordance with the new perspective of PCa pathogenesis.

Topics: Aged; Case-Control Studies; Estradiol; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Metabolic Syndrome; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Testosterone

Leptin, a cytokine produced by the adipose tissue in response to food intake, is a key player in the regulation of energy balance and body weight control. Physiological action of leptin in modulating the metabolic adaptation of different peripheral tissues supports the hypothesis that it could also exert a direct effect on cancer cells. In vitro, treatment with leptin up-regulated HIF-1α and stimulated adhesion and invasion of prostate cancer cells cultured in hypoxia. Leptin action was effective in both low and high glycolytic cancer cell lines, and determined the up-regulation of lactate exporter MCT4 and its associated protein CD147. HIF-1α stabilization was oligomycin-independent and was associated with an important modulation of mitochondrial homeostasis. In fact, leptin treatment produced mitochondrial biogenesis, stabilization of mitochondrial membrane potential and increased uncoupled respiration through the up-regulation of UCP2. Furthermore, leptin counteracted the downmodulation of SIRT1 induced by hypoxia, and persistent high levels of SIRT1 were directly involved in HIF-1α stabilization. Leptin can sustain cancer progression in hypoxic environment and when mitochondrial respiration is impaired. Leptin signaling axis, including the new proposed intermediate SIRT1, could represent a new diagnostic and therapeutic target in prostate cancer.

Topics: Adenocarcinoma; Aged; Basigin; Cell Adhesion; Cell Line, Tumor; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Male; Membrane Potential, Mitochondrial; Middle Aged; Mitochondria; Monocarboxylic Acid Transporters; Muscle Proteins; Neoplasm Invasiveness; Organelle Biogenesis; Prostatic Neoplasms; Protein Stability; RNA Interference; Sirtuin 1; Time Factors; Transfection; Tumor Hypoxia; Tumor Microenvironment; Uncoupling Protein 2; Up-Regulation

To evaluate the correlation between the level of adipocytokines expression in periprostatic adipose tissue and the prostate cancer aggressiveness.. The periprostatic adipose tissues were collected from 30 patients who underwent radical retropubic prostatectomy. The subcutaneous adipose, periprostatic adipose tissues and prostate cancer tissue from the same patient were collected from 10 patients for match research. The expression level of IL-6, Leptin and Adiponectin was detected by immunohistochemistry and by Real-time quantitative PCR in periprostatic adipose tissues.. There were differences in the positive rates of IL-6, Leptin and Adiponectin expression in the periprostate adipose between prostate cancer and control (P<0.001, P=0.032, 0.003). Nothing but the "IL-6 expression intensity" was seen in difference with the aggressiveness of prostate cancer (P=0.001), and was relevant with the prostate cancer aggressiveness (rs=0.668, P<0.001); The mRNA expression of IL-6 in periprostatic adipose tissues of prostate cancer was higher than that of control (P=0.049), and the mRNA expression of Adiponectin was lower (P<0.0001); IL-6 mRNA expression in periprostate adipose tissue and prostate cancer tissue were higher than that in subcutaneous adipose (P<0.001, P=0.001); IL-6 mRNA expression in periprostate adipose was correlated with that in prostate cancer tissue (r=0.663, p=0.036); Adiponectin mRNA expression in prostate cancer tissue was lower than that in periprostate adipose (P=0.006), and Adiponectin mRNA expression in periprostate adipose was correlated with that in prostate cancer tissue (r=0.707, p=0.022).. IL-6, Leptin and Adiponectin were expressed in the periprostatic adipose tissues, which constitute the microenvironment of prostate cancer aggressiveness. There might be intimate relationship between periprostate adipose and prostate cancer tissue.

Topics: Adipokines; Adipose Tissue; Humans; Interleukin-6; Leptin; Male; Prostatic Neoplasms; RNA, Messenger

Prostate cancer (PCa) is one of the most common diseases in men. It is important to assess prognostic factors and whether high cortisol levels and complex hormonal interactions could be responsible for PCa development. We evaluated the relationship between cortisol, leptin and estrogens in 141 men, 71 with PCa and the remaining 70 constituting a low risk group (LRG). They were recruited for this study from a total of 2906 middleaged men (ages 4570 years) who completed an evaluation for prostatic diseases at the Urology Division, Hospital de Clinicas "Jose de San Martin", University of Buenos Aires, in May 2009. In this cross sectional study, cortisol, PSA, totaltestosterone, freetestosterone, bioavailable testosterone, LH and estradiol were measured in serum. We observed increased cortisol levels in PCa patients as compared to LRG cases (p=0.004,). Leptin and estradiol levels were also higher in PCa patients (p=0.048; p<0.0001, respectively). Logistic regression analysis indicated that serum cortisol (OR: 1.110 (95% CI 1.0161.213), p=0.022), estradiol (OR: 1.044 (95% CI 1.0081.081), p=0.016) and leptin (OR: 1.248 (95% CI 1.0481.487), p=0.013) explained 27% of the variance of dependent variables, even after adjusting for age, smoking, BMI and waist circumference. We found increased cortisol levels in PCa patients as compared to LRG, as well as an altered circulating hormonal profile.

Topics: Aged; Follow-Up Studies; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Neoplasm Grading; Prognosis; Prostatic Neoplasms; Radioimmunoassay; Risk Factors; Testosterone; Waist Circumference

The present study was designed to investigate the effect of leptin on estrogen metabolism in prostatic cells.. Malignant (PC-3) and benign (BPH-1) human prostate cells were treated with 17-β-hydroxyestradiol (1 μM) alone or in combination with leptin (0.4, 4, 40 ng/ml) for 72 h. Cell proliferation assay, immunocytochemical staining of estrogen receptor (ER), liquid chromatography-tandem mass spectrometry method (LC-MS) and semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) were used.. Cell proliferation assay demonstrated that leptin caused significant growth potentiation in both cells. Immunocytochemical staining showed that leptin significantly increased the expression of ER-α and decreased that of ER-β in PC-3 cells. LC-MS method revealed that leptin increased the concentration 4-hydroxyestrone and/or decreased that of 2-methoxyestradiol, 4-methoxyestradiol and 2-methoxyestrone. Interestingly, RT-PCR showed that leptin significantly up-regulated the expression of aromatase and cytochrome P450 1B1 (CYP1B1) enzymes; however down-regulated the expression of catechol-o-methyltransferase (COMT) enzyme.. These data indicate that leptin-induced proliferative effect in prostate cells might be partly attributed to estrogen metabolism. Thus, leptin might be a novel target for therapeutic intervention in prostatic disorders.

Topics: Cell Line, Tumor; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Gene Expression; Humans; Leptin; Male; Prostate; Prostatic Neoplasms

Obesity correlates with an increased risk of developing prostate cancer (PCa) and leptin plays an important role in PCa progression. Since leptin is produced by adipocytes, the serum leptin level is higher in obese than in non-obese individuals. However, the effects of leptin remain controversial and unclear. The aim of the present study was to investigate the effect of leptin on PCa cell aggressiveness. Three human PCa cell lines (LNCaP, DU145 and PC-3) were treated with recombinant leptin for 28 days. Cell proliferation, migration, and invasion were estimated using the WST assay, a wound-healing assay, and a BD Matrigel invasion assay, respectively. The mechanism underlying the proliferative effect of leptin was investigated by cell transfections with small interfering RNA (siRNA) against the leptin receptor (ObR) or forkhead box O1 (FOXO1), and by immunocytochemistry. Long-term exposure of PCa cells to leptin enhanced their proliferation, migration and invasion. Leptin increased ObR expression and enhanced Akt phosphorylation constitutively. Leptin also increased the phosphorylation of FOXO1 via PI3K signaling and FOXO1 gene silencing enhanced PCa cell proliferation. Leptin induced the translocation of FOXO1 from the nucleus to the cytoplasm. Furthermore, the PI3K inhibitor, LY294002 suppressed this translocation. These results suggested that leptin regulated the subcellular localization of FOXO1 and induced Akt phosphorylation. Additionally, we revealed that leptin increased the expression of cyclin D1 and decreased the expression of p21 protein. In conclusion, long-term exposure to leptin increased the cell proliferation, migration, and invasion of PCa cells through inactivation of FOXO1. This inactivation resulted from exclusion of FOXO1 from the nucleus and its restriction to the cytoplasm through PI3K/Akt signaling. Our findings contribute to an understanding of the association between obesity and PCa aggressiveness.

Topics: Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Obesity; Phosphorylation; Prostatic Neoplasms; Receptors, Leptin; RNA, Small Interfering; Signal Transduction

Obesity has been associated with increased incidence and risk of mortality of prostate cancer. One of the proposed mechanisms underlying this risk association is the change in adipokines expression that could promote the development and progression of the prostate tumor cells. The main goal of this study was to evaluate the effect of preadipocyte and adipocyte secretome in the proliferation, migration and invasion of androgen independent prostate carcinoma cells (RM1) and to assess cell proliferation in the presence of the adiposity signals leptin and insulin. RM1 cells were co-cultured in with preadipocytes, adipocytes or cultured in their respective conditioned medium. Cell proliferation was assessed by flow cytometry and XTT viability test. Cell migration was evaluated using a wound healing injury assay of RM1 cells cultured with conditioned media. Cellular invasion of RM1 cells co-cultured with adipocytes and preadipocytes was assessed using matrigel membranes. Preadipocyte conditioned medium was associated with a small increase in RM1 proliferation, while adipocytes conditioned media significantly increased RM1 cell proliferation (p<0.01). Adipocytes also significantly increased the RM1 cells proliferation in co-culture (p <0.01). Cell migration was higher in RM1 cells cultured with preadipocyte and adipocyte conditioned medium. RM1 cell invasion was significantly increased after co-culture with preadipocytes and adipocytes (p <0.05). Insulin also increased significantly the cell proliferation in contrast to leptin, which showed no effect. In conclusion, prostate carcinoma cells seem to be influenced by factors secreted by adipocytes that are able to increase their ability to proliferate, migrate and invade.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Culture Media, Conditioned; Flow Cytometry; Insulin; Leptin; Male; Mice; Prostatic Neoplasms

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.

Topics: Animals; Blood Glucose; Cell Division; Circadian Rhythm; Corticosterone; Fatty Acids; Humans; Insulin; Lactic Acid; Leptin; Light; Male; Melatonin; Prostatic Neoplasms; Rats; Rats, Nude

Insulin-like growth factor (IGF) and adipokines have been implicated in prostate cancer carcinogenesis.. Data from 122 men with serum samples drawn within 3 months of starting ADT for metastatic prostate cancer was accessed retrospectively. IGF-1, IGF binding protein (BP)-1, leptin, and adiponectin levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to castration resistant prostate cancer (CRPC) and overall survival by the protein levels, adjusted for clinical variables, age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, extent of metastases and were reported as hazard ratio (HR) with 95% confidence interval (CI).. Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥ 1 vs. 0) was negatively associated with overall survival [H  = 2.8 (1.1-7.0), P = 0.03], and PSA nadir <0.2 was predictive of longer time to CRPC [HR = 0.3 (0.2-0.5), P < 0.0001]. The median time to CRPC by low, middle, and top IGFBP-1 tertile distribution was 20.7, 18.1, and 12.4 months, respectively, with HR for middle versus low tertile levels 3.1 (1.7-5), P = 0.0003, and for top versus low tertile levels was 2.4 (1.3-4.2), P = 0.003. The median overall survival by low, middle and top tertile IGFBP-1 level was 48.5, 46.4, and 32.8 months, respectively, with HR for top versus low tertile 2.5 (1.2-5.1), P = 0.01. There was no association with IGF-1, adiponectin and leptin.. Elevated IGFBP-1 appears to be associated with shorter time to CRPC and lower overall survival in men with metastatic prostate cancer.

Topics: Adiponectin; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Insulin-Like Growth Factor Binding Protein 1; Leptin; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Time Factors

The relationship between obesity and prostate cancer aggressiveness is controversial in recent studies, partly because BMI is the only generally applied marker of obesity. Our study aimed at evaluating the correlation of periprostatic fat (PF) on magnatic resonance imaging (MRI) and adipocytokines with prostate cancer aggressiveness.. A total of 184 patients who underwent radical retropubic prostatectomy (RRP) were analyzed retrospectively; different fat measurements on MRI slices and levels of adipocytokines were compared with the clinical and pathologic factors using SSPS ver.13.0.. The PF rates showed a statistically significant variation (p=0.019, 0.025) among groups, that is to say, more adipose tissue was distributed in periprostatic areas of high risk patients. Logistic regression analysis adjusted for age revealed a statistically association between the PF, the ratio and the risk of having high-risk disease (p=0.031, 0.024). The levels of IL-6, leptin and c-reactive protein (CRP) significantly increased with the aggressiveness of prostate cancer, and also with PF and its ratio. The strongest correlation was seen between IL-6 and PF (Pearson r coefficient=0.67, P<0.001). No association was observed between adipocytokines and BMI.. Periprostatic adiposity not only affects prostate cancer aggressiveness, but also influences the secretion of adipocytokines. IL-6, PF and CRP have promoting effects on progression of prostate cancer.

Topics: Adipokines; Adipose Tissue; Adiposity; Aged; Body Mass Index; C-Reactive Protein; Disease Progression; Humans; Interleukin-6; Leptin; Male; Obesity; Prostate; Prostatectomy; Prostatic Neoplasms; Retrospective Studies

Hyperinsulinemia is hypothesized to influence prostate cancer risk. Thus, we evaluated the association of circulating C-peptide, which is a marker of insulin secretion, and leptin, which is secreted in response to insulin and influences insulin sensitivity, with prostate cancer risk.. We identified prostate cancer cases (n = 1,314) diagnosed a mean of 5.4 years after blood draw and matched controls (n = 1,314) in the Health Professionals Follow-up Study. Plasma C-peptide and leptin concentrations were measured by ELISA. Odds ratios (ORs) and 95 % confidence intervals (CI) were estimated taking into account the matching factors age and history of a PSA test before blood draw and further adjusting for body mass index, diabetes, and other factors.. Neither C-peptide (quartile [Q]4 vs. Q1: OR 1.05, 95 % CI 0.82-1.34, p-trend = 0.95) nor leptin (Q4 vs. Q1: OR 0.85, 95 % CI 0.65-1.12, p-trend = 0.14) was associated with prostate cancer risk. Further, neither was associated with risk of advanced or lethal disease (n = 156 cases; C-peptide: Q4 vs. Q1, OR 1.18, 95 % CI 0.69-2.03, p-trend = 0.78; leptin: Q4 vs. Q1, OR 0.74, 95 % CI 0.41-1.36, p-trend = 0.34).. In this large prospective study, circulating C-peptide and leptin concentrations were not clearly associated with risk of prostate cancer overall or aggressive disease. Well into the PSA era, our findings do not appear to be supportive of the hypothesis that hyperinsulinemia influences risk of total or aggressive prostate cancer.

Topics: Aged; C-Peptide; Case-Control Studies; Cell Growth Processes; Cohort Studies; Follow-Up Studies; Humans; Incidence; Leptin; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Risk Factors; Surveys and Questionnaires

The aim of this study was to evaluate the expression of leptin and its receptor in histological sections of prostate tumors, and their association with prognostic factors.. A total of 532 surgical specimens from prostate cancer were studied. After histopathological diagnosis, the samples were included in tissue microarrays containing cores from tumor and non-tumor (benign prostatic hyperplasia) areas. These were immunostained with anti-leptin and anti-leptin-receptor antibodies. Objective and subjective analyses were performed. Student's-t-test and ANOVA were used to compare mean values, and linear regression was used to evaluate the correlation between histological results and prognostic indicators.. Leptin receptor expression was reduced in tumors with a positive surgical margin, urethral margin involvement, and seminal vesicles invasion. Further, there was a negative correlation between the expression of leptin receptor in tumor areas and the sum of prognostic factors, suggesting that leptin receptor may predict the aggressiveness of disease.. Our findings suggest that leptin receptor expression is a potential prognostic factor for PCa. Further investigation is needed to support the use of leptin receptor as a novel biomarker, although leptin itself does not seem to predict the aggressiveness of prostate cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Humans; Leptin; Male; Middle Aged; Prognosis; Prostatic Neoplasms; Receptors, Leptin; Seminal Vesicles; Tissue Array Analysis

Prostate cancer (CaP) in India is the 10th most common malignancy affecting men. CaP incidence in India is low, but rising like other countries. The reasons for this racial disparity are uncertain. The foremost reasons that may underlie regional/ethnic differences are genetic polymorphisms, altered hormonal status, socioeconomic status, and obesity. This study aimed at investigating the role of adipocytokines in stimulating the promotion and progression of CaP.. A cross-sectional study on histopathologically proven prostate cancer (N=95) and benign prostatic hyperplasia (N=95) patients was undertaken. CaP patients were classified into high-grade (N=62) and low-grade (N=33), and high stage (N=31) and low stage (N=64) groups. The level of body mass index (BMI), waste to hip ratio (WHR), interleukin-6 (IL-6), leptin, and adiponectin were compared between BPH and CaP groups and between grades and stages of prostate cancer.. The level of BMI was significantly (p<0.001) higher in CaP patients (26.58±4.76) in comparison to BPH (22.15±2.90). Similarly, WHR was significantly (p<0.0001) higher in the CaP patients (1.08±0.37) in comparison to BPH (0.86±0.15). Leptin (BPH: 25.60, CaP: 56.00) and II-6 levels (BPH: 9.90, CaP: 32.30) were significantly higher, but adiponectin was significantly lower in CaP patients as compared to BPH. High grade CaP patients had significantly higher BMI and WHR in comparison to low grade, and WHR was also higher in high stage CaP. Leptin and IL-6 level were higher in high stage and high grade, but adiponectin was low in high stage and high grade groups in comparison to low stage and low grade groups.. Higher BMI and WHR correlate with prostate cancer independently, suggesting obesity to be a promoter of poor prostate health. Leptin and IL-6 appear to have stimulating effect on prostate cancer cells inducing the promotion and progression of CaP, but adiponectin appears to be protective against prostate cancer.

Topics: Adipokines; Adiponectin; Aged; Biomarkers, Tumor; Body Mass Index; Cross-Sectional Studies; Disease Progression; Humans; India; Interleukin-6; Leptin; Male; Obesity; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Waist-Hip Ratio

Obesity has been associated with an increased risk of advanced and fatal prostate cancer; adipokines may mediate this association. We examined associations of the adipokines leptin and adiponectin with the stage and grade of PSA-detected prostate cancer.. We conducted a nested case-control study comparing 311 men with mainly locally advanced (≥T3, N1, or M1 cases) vs. 413 men with localized (T ≤2 & NX-0 & M0 controls) PSA-detected prostate cancer, recruited 2001-2009 from 9 UK regions to the ProtecT study. Associations of body mass index and adipokine levels with prostate cancer stage were determined by conditional logistic regression and with grade (Gleason score ≥7 vs. ≤6) by unconditional logistic regression.. Adiponectin was inversely associated with prostate cancer stage in overweight and obese men (OR 0.62; 95 % CI 0.42-0.90; p = 0.01), but not in normal weight men (OR 1.48; 0.77-2.82; p = 0.24) (p for interaction 0.007), or all men (OR 0.86; 0.66-1.11; p = 0.24). There was no compelling evidence of associations between leptin or leptin to adiponectin ratio and prostate cancer stage. No strong associations of adiponectin, leptin, or leptin:adiponectin ratio with grade were seen.. This study provides some evidence that adiponectin levels may be associated with prostate cancer stage, dependent on the degree of adiposity of the man. Our results are consistent with adiponectin countering the adverse effects of obesity on prostate cancer progression.

Topics: Adiponectin; Aged; Case-Control Studies; Humans; Leptin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms

Non-steroidal anti-inflammatory drug-activated gene (NAG-1), a divergent member of the transforming growth factor-beta superfamily, has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis. Recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D) of the NAG-1 protein is associated with lower human prostate cancer incidence. The objective of the current study is to investigate the activity of NAG-1 H6D variant in prostate cancer tumorigenesis in vivo.. Human prostate cancer DU145 cells expressing the H6D NAG-1 or wild-type (WT) NAG-1 were injected subcutaneously into nude mice and tumor growth was monitored. Serum and tumor samples were collected for subsequent analysis.. The H6D variant was more potent than the WT NAG-1 and inhibited tumor growth significantly compared to control mice. Mice with tumors expressing the WT NAG-1 have greater reduced both body weight and abdominal fat than mice with H6D variant tumors suggesting different activities of the WT NAG-1 and the H6D NAG-1. A significant reduction in adiponectin, leptin, and IGF-1 serum levels was observed in the tumor-bearing mice with a more profound reduction observed with expression of H6D variant. Cyclin D1 expression was suppressed in the tumors with a dramatic reduction observed in the tumor expressing the H6D variant.. Our data suggest that the H6D variant of NAG-1 inhibits prostate tumorigenesis by suppressing IGF-1 and cyclin D1 expression but likely additional mechanisms are operative.

Topics: Adiponectin; Alleles; Animals; Cell Line, Tumor; Cyclin D1; Growth Differentiation Factor 15; Humans; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Nude; Neoplasm Transplantation; Polymorphism, Single Nucleotide; Prostate; Prostatic Neoplasms; Transplantation, Heterologous

The association between obesity and cancer is controversial: whereas several epidemiological, clinical and research studies using cancer cell lines have supported that high levels of insulin and leptin could favor prostate cancer development and dissemination, other studies have demonstrated opposite effects or even absence of association. The main goal of this study was to evaluate the in vitro proliferation of murine androgen insensitive prostate carcinoma cells RM1 in the presence of leptin and insulin. After assessing and confirming the presence of leptin and insulin receptors in RM1 cells by immunocytochemistry, cells were cultured in the presence of different concentrations of leptin (0, 25, 50, 100 and 200 ng/mL), insulin (0, 50, 100, 150 and 200 nM) or leptin plus insulin ( 25 ng/ml + 50 nM; 50 ng/ml + 100 nM; 100 ng/ml + 150 nM; 200 ng/ml + 200 nM; 25 ng/ml + 150 nM; 100 ng/ml + 50 nM of leptin plus insulin, respectively). Cell proliferation was evaluated by assessing the percentage of resazurin reduction, a surrogate marker of cell metabolic rate. Leptin significantly decreased the percentage of resazurin reduction in all studied concentrations while there was only a slight or non significant difference in RM1cell proliferation in the presence of insulin or insulin combined with leptin when compared with control. These results show that leptin decreases RM1 prostate cancer cell proliferation at the studied concentrations, while insulin is able to antagonize the leptin inhibition of RM1 prostate cancer cell growth in vitro. The difference in cell growth that is modulated by the various hormonal environments may explain the heterogeneous behavior of prostate cancer in the obese human population.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Mice; Prostatic Neoplasms

For some years now, reduced testosterone levels have been related to obesity, insulin resistance, type 2 diabetes, heart disease, benign prostatic hypertrophy and even prostate cancer--often considered guilty more by association, than actual cause--with little attention paid to the important role of increased intracellular oestrogen, in the pathogenesis of these chronic diseases. In the final stage of the steroidogenic cascade, testosterone is metabolised to oestradiol by P450 aromatase, in the cytoplasm of adipocytes, breast cells, endothelial cells and prostate cells, to increase intracellular oestradiol concentration at the expense of testosterone. It follows therefore, that any compound that up-regulates aromatase, or any molecule that mimics oestrogen, will not only increase the activation of the mainly proliferative, classic ER-α, oestrogen receptors to induce adipogenesis and growth disorders in oestrogen-sensitive tissues, but also activate the recently identified transmembrane G protein-coupled oestrogen receptors (GPER), and deleteriously alter important intracellular signalling sequences, that promote mitogenic growth and endothelial damage. This paper simplifies how stress, xeno-oestrogens, poor dietary choices and reactive toxins up-regulate aromatase to increase intracellular oestradiol production; how oestradiol in combination with leptin and insulin cause insulin resistance and leptin resistance through aberrant serine phosphorylation; how the increased oestradiol, insulin and leptin stimulate rapid, non-genomic G protein-coupled phosphorylation cascades, to increase fat deposition and create the vasoconstrictive, dyslipidemic features of metabolic syndrome; how aberrant GPER signalling induces benign prostatic hypertrophy; and how increased intracellular oestradiol stimulates mitogenic change and tumour-cell activators, to cause prostate cancer. In essence, the up-regulation of aromatase produces increased intracellular oestradiol, increases ER-α activation and increases GPER activation, in combination with insulin, to cause aberrant downstream transduction signaling, and thus induce metabolic syndrome and mitogenic prostate growth. To understand this fact, that raised intracellular oestradiol levels in men, induce and promote obesity, gynecomastia, metabolic syndrome, type two diabetes, benign prostatic hypertrophy and prostate cancer, rather than low testosterone, represents a shift in medical thinking, a new awareness, that will reduce

Topics: Adiposity; Aromatase; Body Fat Distribution; Diabetes Mellitus, Type 2; Estrogen Receptor alpha; Estrogens; Gynecomastia; Humans; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Obesity; Phosphorylation; Prostatic Diseases; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction; Testosterone; Up-Regulation

Obesity is associated with larger tumors, shorter time to PSA failure, and higher Gleason scores. However, the mechanism(s) by which obesity promotes aggressive prostate cancer remains unknown. We hypothesize that circulating factors related to obesity promote prostate cancer progression by modulating components of the metastatic cascade.. Male C57BL/6 mice (6 weeks) were fed an ad libitum diet-induced obesity (60% fat) or control diet (10% fat) for 12 weeks. Serum was collected, metabolic and inflammatory proteins were measured by an antibody array. Sera were used to measure, in vitro, characteristics of a metastatic phenotype.. Comparable to obese men, obese sera contained higher levels or leptin, vascular endothelial growth factor, PAI-1, interleukin-6 (IL-6) and lower levels of testosterone. In prostate cells, serum was used to assess: proliferation, invasion, migration, epithelial-mesenchymal-transition (EMT) and matrix metalloproteinase (MMP) activity. LNCaP and PacMetUT1 cells exposed to obese sera increased proliferation, whereas PrEC and DU145 were unaffected. LNCaP, PacMetUT1 and DU145 cancer cells exposed to obese sera resulted in increased invasion, migration and MMP-9 activity. Prostate cancer cells exposed to obese sera showed increased vimentin, dispersion of e-cadherin and β-catenin from the plasma membrane.. We report, prostate cancer cells exposed to sera from obese mice increases proliferation, invasion, migration, MMP activity and induces changes in proteins critical for EMT.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Interleukin-6; Leptin; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Obese; Neoplasm Invasiveness; Neoplasm Metastasis; Obesity; Plasminogen Activator Inhibitor 1; Prostate; Prostatic Neoplasms; Testosterone; Vascular Endothelial Growth Factor A

Adiponectin and leptin, polypeptide hormones produced by adipocytes, have recently been reported to be associated with prostate cancer risk, though, the relationship remains poorly understood. We examined the association of adiponectin and leptin levels in serum with prostate cancer risk after adjustments for age, obesity-related factors, and prostate cancer risk.. Fifty-four prostate cancer patients and 70 control subjects provided blood sampled between 2008 and 2009. Using those, we determined serum adiponectin and leptin levels, and evaluated their relationships with prostate cancer risk after adjustments for age, obesity-related factors (body weight, body mass index, waist circumference), and prostate volume. Adipokine densities were calculated by dividing serum level with prostate volume.. There were no differences for median serum adiponectin and leptin levels between the prostate cancer and benign control groups (P=0.22 and 0.78, respectively). Patients with levels of both adipokines in the highest quartile after adjustment for age had significantly higher risks of prostate cancer (adiponectin: odds ratio [OR] 2.79, P=0.014; leptin: OR 2.72, P=0.027). Patients with an adiponectin level greater than the median after adjustment for body weight also had a significantly elevated risk of prostate cancer (OR 2.22, P=0.031), whereas, those with a leptin level significantly greater than the median had a significantly lower risk (OR 0.46, P=0.027). Furthermore, median adiponectin density was significantly higher in the prostate cancer group than the benign group (P=0.0033).. Serum adiponectin and leptin levels are useful markers for prostate cancer risk after adjustments for age, obesity-related factors, and prostate volume.

Topics: Adiponectin; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Early Detection of Cancer; Humans; Leptin; Male; Middle Aged; Obesity; Organ Size; Prostate; Prostatic Neoplasms; Risk Factors

Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. The aim of this study was to investigate whether leptin is associated with the motility of prostate cancer cells. We found that leptin increased the migration of human prostate cancer cells and expression of αvβ3 integrin on these cells. Leptin-mediated migration and increased integrin expression were attenuated by OBRl receptor antisense oligonucleotide (ODN). Activation of insulin receptor substrate (IRS-1), phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB pathways after leptin treatment was demonstrated. Furthermore, leptin-induced integrin expression and migration activity were inhibited by specific inhibitors; small interfering RNAs (siRNAs); and mutants of the IRS-1, PI3K, Akt, and NF-κB cascades. Therefore, this study shows that leptin stimulates the migration of human prostate cancer cells, one of the mechanisms underlying leptin-directed migration was transcriptional up-regulation of αvβ3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-κB signal transduction pathway.

Topics: Cell Line, Tumor; Cell Movement; Genes, Reporter; Humans; Insulin Receptor Substrate Proteins; Integrin alphaVbeta3; Leptin; Male; Mutation; Neoplasm Invasiveness; NF-kappa B; Oligonucleotides, Antisense; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptors, Leptin; RNA Interference; Signal Transduction; Time Factors; Transcription, Genetic; Transfection; Up-Regulation

We hypothesize that racial differences in utero contribute to the racial disparity in prostate cancer risk. Leptin is a candidate for evaluating this hypothesis because it influences fetal development and newborn growth.. We measured leptin concentration by ELISA in venous cord blood collected from 70 African-American and 37 white male full-term babies. We measured sex steroid hormones and insulin-like growth factor (IGF) axis concentrations previously. Separately by race, we calculated the geometric mean leptin concentration and estimated the geometric mean adjusted for birth and placental weights, mother's age and parity, time of day and season of birth, and sex steroid hormone and IGF axis concentrations by linear regression.. Leptin was positively correlated with birth (r = 0.34) and placental (r = 0.25) weights, IGF-1 (r = 0.21), and IGF binding protein-3 (r = 0.29) adjusting for race. Unadjusted geometric mean leptin did not differ (P = 0.92) between African Americans (5,280 pg/mL; 95% CI: 4,322-6,451) and whites (5,187 pg/mL; 95% CI: 3,938-6,832). Adjusted geometric mean leptin was nonstatistically significantly higher (P = 0.15) in African Americans (5,954 pg/mL; 95% CI: 4,725-7,502) than in whites (4,133 pg/mL; 95% CI: 2,890-5,910).. We observed a nonsignificantly higher adjusted cord blood leptin concentration in African-American male babies than in white male babies, although unadjusted levels were similar.. These findings do not support the hypothesis that leptin level in utero contributes to the racial disparity in prostate cancer risk in adulthood.

Topics: Black or African American; Enzyme-Linked Immunosorbent Assay; Ethnicity; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Leptin; Male; Pregnancy; Prostatic Neoplasms; Sex Factors; White People

Prostate cancer (PCa) progression is often associated with transactivation of the androgen receptor (AR) by endogenous hormones/growth factors. One such factor affecting growth, proliferation, and apoptostis (pro-/anti-) in various cancers is the adipokine leptin. This research studied leptin-induced signaling and apoptosis in androgen sensitive (LNCaP, PC3/AR) and insensitive (PC3, DU145) PCa cell lines.. Signaling was studied by immunoblotting in cells overexpressing leptin receptors (LRb), Janus kinase 2 (JAK2), and kinase negative-HER2-YFP cDNAs. Apoptosis was measured by immunoblotting of apoptotic proteins and by Hoechst staining of condensed DNA.. Leptin rapidly induced activation of JAK2, STAT3, and MAPK (ERK1/2) signaling cascades; it may also induce HER2 transactivation via leptin-induced phospho-JAK2. Leptin was then shown to exert clear pro-apoptotic effects, increasing levels of caspase 3, cleavage of its substrate, poly (ADP-ribose) polymerase (PARP) to cleaved PARP(89) , levels of CK 18, a cytoskeletal protein formed during apoptosis, and DNA condensation. Kinase inhibitors indicated that leptin-induced apoptosis is probably mediated by balanced activation of JAK2/STAT3, p38 MAPK, and PKC pathways in PCa cells. A human leptin mutein LRb antagonist, L39A/D40A/F41A, fully inhibited leptin-induced phosphorylation of JAK2, ERK1/2, and Akt/PKB, and partially abrogated effects on apoptotic proteins. In LNCaP and PC3/AR cells, leptin increased AR protein levels in correlation with raised apoptotic markers. Thus, AR may mediate, at least partly, the leptin-induced apoptotic response.. Leptin can clearly induce apoptosis in human PCa cell lines. These findings could lead to development of new leptin agonists with enhanced pro-apoptotic effects and targeted for use in human PCa.

Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Cell Survival; Humans; Immunoblotting; Keratin-18; Leptin; Male; Mitogen-Activated Protein Kinases; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Protein Kinase Inhibitors; Receptors, Androgen; Receptors, Leptin; Signal Transduction

The aims of this study are to (1) study the influence of polymorphisms in adiponectin gene on adiponectin levels and potential associations with breast, prostate and colon cancer; (2) investigate the associations of adiponectin levels with other adipokines and breast, prostate and colon cancers.. We measured fasting adiponectin, leptin, insulin, Sex steroids in 132 (66 females, 66 males) cancer patients and 68 age and sex matched apparently healthy subjects. Body Mass Index (BMI) and waist circumference were used as indices of obesity. Insulin Resistance was assessed using Homeostasis Model Assessment (HOMA). Three single nucleotide polymorphisms (SNP rs182052 (G-10066-A), SNP rs1501299 (276G > T), SNP rs224176 (45T > G) in adiponectin gene were studied using Real Time Polymerase Chain Reaction.. GG genotype of SNP rs1501299 was significantly associated with higher levels of adiponectin (OR=1.2, 95%CI(1.03-1.3), p = 0.02); breast (OR=8.6, 95%CI(1.03-71), p = 0.04), colon cancers (OR= 12, 95%CI(1.2-115), p =0.03). GT genotype was also associated significantly with colon cancer (OR=2.6, 95%CI (1.1-6), p =0.03). However SNP rs224176 was associated with only breast cancer.. Our results demonstrate that adiponectin gene SNP rs1501299 and SNP rs224176 may be the predisposing factors in some cancers but our results differ from what has been reported in other populations suggesting a complex relationship between genetic variations and phenotypic adiponectin levels.

Topics: Adiponectin; Adult; Aged; Body Mass Index; Breast Neoplasms; Case-Control Studies; Colonic Neoplasms; Female; Genetic Predisposition to Disease; Gonadal Steroid Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Risk Factors; Waist Circumference

Adipocytokines may mediate the association between adiposity and lethal prostate cancer outcomes.. In the Physicians' Health Study, we prospectively examined the association of prediagnostic plasma concentrations of adiponectin and leptin with risk of developing incident prostate cancer (654 cases diagnosed 1982-2000 and 644 age-matched controls) and, among cases, risk of dying from prostate cancer by 2007.. Adiponectin concentrations were not associated with risk of overall prostate cancer. However, men with higher adiponectin concentrations had lower risk of developing high-grade or lethal cancer (metastatic or fatal disease). The relative risk (95% CI) comparing the highest quintile to the lowest (Q5 vs Q1) was 0.25 (95% CI 0.07-0.87; P(trend) = 0.02) for lethal cancer. Among all the cases, higher adiponectin concentrations predicted lower prostate cancer-specific mortality [hazard ratio (HR)(Q5 vs Q1)= 0.39; 95% CI 0.17-0.85; P(trend) = 0.02], independent of body mass index (BMI), plasma C-peptide (a marker of insulin secretion), leptin, clinical stage, and tumor grade. This inverse association was apparent mainly among men with a BMI >or=25 kg/m(2) (HR(Q5 vs Q1)= 0.10; 95% CI 0.01-0.78; P(trend) = 0.02), but not among men of normal weight (P(trend) = 0.51). Although the correlation of leptin concentrations with BMI (r = 0.58, P < 0.001) was stronger than that of adiponectin (r = -0.17, P < 0.001), leptin was unrelated to prostate cancer risk or mortality.. Higher prediagnostic adiponectin (but not leptin) concentrations predispose men to a lower risk of developing high-grade prostate cancer and a lower risk of subsequently dying from the cancer, suggesting a mechanistic link between obesity and poor prostate cancer outcome.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; AMP-Activated Protein Kinases; Body Mass Index; Humans; Leptin; Logistic Models; Male; Middle Aged; Obesity; Prospective Studies; Prostatic Neoplasms; Risk Factors

Obesity is considered to be a risk factor for prostate cancer. Mitogenic actions of leptin, an adipocyte-derived hormone in a variety of cancer cell types have been identified. We have investigated the proliferative effects of leptin on human prostate cancer cells and assessed the role of tyrosine kinase signalling in mediating these actions.. Two human androgen-resistant prostate cancer cell lines and one androgen-sensitive human prostate adenocarcinoma cell line were treated with leptin (5-100 ng / mL) for up to 48 hours. Under serum-free conditions, cell proliferation was measured using an enzyme-linked colorimetric assay. Furthermore, phosphorylation of a downstream component of MAPK (ERK1 / 2) was detected by Western blotting and a specific inhibitor of MAPK (PD98059; 40 microM) was used to evaluate the role of this signalling pathway.. Leptin dose-dependently increased the cell number in both androgen-resistant cell lines after 24 h and 48 h of incubation (percent of control: DU145 = 194.6 +/- 5.9 %, PC-3 = 177.9 +/- 6.8 %; 100 ng / mL leptin; 48 h; p < 0.001). Conversely, leptin's proliferative effect on the androgen-sensitive cell line was less pronounced (percent of control: LNCaP = 112.3 +/- 6.1 %; 100 ng / mL leptin; 48 h). Leptin also caused dose-dependent ERK1 / 2 phosphorylation in both androgen-resistant cell lines. In addition, pre-treatment with PD98059 inhibited these responses and attenuated leptin's mitogenic action.. Data from this in vitro study suggest an association between obesity-associated hyperleptinemia and an increased risk for prostate cancer. Further investigations are necessary to clarify whether these data have clinical relevance regarding the use as a prognostic marker for predicting the timing of the occurrence of androgen resistency.

Topics: Adenocarcinoma; Adipokines; Blotting, Western; Cell Division; Cell Line, Tumor; Cell Transformation, Neoplastic; Humans; In Vitro Techniques; Leptin; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Neoplasms, Hormone-Dependent; Obesity; Phosphorylation; Prostatic Neoplasms; Protein-Tyrosine Kinases; Risk Factors; Signal Transduction

Plasma insulin concentration is increased in prostate cancer patients during androgen deprivation therapy (ADT) and hyperinsulinemia has been associated with aggressive prostate cancer behavior. To investigate the possible role of castration-induced hyperinsulinemia as a mechanism that may attenuate the beneficial effects of ADT in patients with prostate cancer, a murine model would be useful. We therefore investigated long-term metabolic effects of castration in several mouse models.. We studied the long-term influence of castration on energy intake, body weight, glucose tolerance, plasma-insulin, plasma insulin-like growth factor-1 (IGF-1), plasma adiponectin, and plasma leptin in C57BL/6, Swiss nu/nu, and CB17 scid mice receiving various diets. In each case, mice were randomized to have either bilateral orchiectomy or a sham operation.. Energy intake, body weight, blood glucose levels in glucose tolerance test, plasma insulin, plasma IGF-1, and plasma leptin level in all had a trend to be decreased in castrated as compared to sham operated mice. Plasma adiponectin level was increased in the castrated mice.. The effects of castration on glucose, insulin, and related markers in several mouse models studied does not coincide with clinical observations; further studies in this area will require clinical research and/or the use of alternate models such as the dog.

Topics: Adiponectin; Androgens; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Energy Intake; Glucose Tolerance Test; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Random Allocation

Obesity has been associated with increased incidence and aggressiveness of prostate cancer. Although controversial, several studies suggest that leptin could influence tumour cell growth and proliferation. The main goal of this study was to assess cellular growth of prostate adenocarcinoma cells in obese mice with different endogenous hormonal environments in what relates to leptin circulating levels and sensitivity. Four groups of mice (n = 6/group) were used, namely obese mice with congenital non-functioning leptin receptor OBR (db/db), obese mice with congenital leptin deficiency (ob/ob), mice with diet induced obesity (DIO) and normal weight C57BL/6J mice (control). All groups of mice were injected subcutaneously with 3.0 x 10(5) RM1 cells/500 microl PBS (murine prostate carcinoma androgen insensitive cells) and tumour growth and angiogenesis were evaluated 14 days after inoculation. The tumours induced in ob/ob and DIO mice were significantly larger (P < 0.001) while those induced in db/db mice were significantly smaller (P = 0.047), when compared with controls. Morphometric analysis revealed that mitotic index and Ki-67 positive nuclear density, both cell proliferation markers, were also significantly lower in the tumours of db/db mice (P < 0.001) when compared to controls. An inverse correlation was observed between leptin plasma levels and tumour weight (r = -0.642, P < 0.001), mitotic index (r = -0.646, P < 0.01) and Ki-67 positive nuclear density (r = -0.795, P < 0.001). These results suggest that high leptin concentrations are not favourable to RM1 cell growth and proliferation. On the contrary, high plasma leptin levels were associated with less cellular proliferation and angiogenesis in vivo.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Ki-67 Antigen; Leptin; Male; Mice; Mice, Inbred C57BL; Mitotic Index; Mutation; Neovascularization, Pathologic; Obesity; Prostatic Neoplasms; Receptors, Leptin; Time Factors; Tumor Burden

Laparoscopic surgery has been proposed to reduce surgical trauma and diminish patients' stress response.. To investigate the role of the adipocytokine, in combination with changes in other known inflammatory markers, in patients undergoing radical prostatectomy.. A total of 580 patients were enrolled in this prospective study. Laparoscopic extraperitoneal radical prostatectomy (LRP) was performed in 286 patients, and open retropubic radical prostatectomy (RRP) in 294 patients.. Blood samples were collected preoperatively and up to 5 d postoperatively.. Serum concentrations of acute phase markers, interleukins (IL), and the adipocytokine leptin were measured at each time point by means of enzyme-linked immunosorbent assay. Clinical data were collected and analysed.. Patients undergoing LRP had significantly lower IL-6 and adipocytokine levels at all measurement time points. However, biphasic kinetics of adipocytokine serum levels were observed during the postoperative course in all patients. LRP was associated with less adipocytokine and IL-6 release, indicating a smaller degree of surgical insult and the minimal invasive nature of this procedure. The limitation of this study was its nonrandomised design.. Adipocytokines might serve as additional immunologic markers of invasiveness in major urologic surgery.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Humans; Inflammation; Interleukin-10; Interleukin-6; Leptin; Male; Middle Aged; Minimally Invasive Surgical Procedures; Postoperative Complications; Prostatectomy; Prostatic Neoplasms; Serum Amyloid A Protein

High expression of leptin receptors have been observed in the prostate cancer in various clinical studies; however the association of serum leptin with carcinoma prostate remains unresolved. We studied association, between serum leptin and carcinoma prostate in Asian (Indian) population and its association with obesity.. 30 prospective cases of cancer prostate and 30 age matched controls were included in this study. Body mass index (BMI) was estimated and categorized in 4 groups by WHO criteria. Waist hip ratio (WHR) was calculated and divided into three groups. Serum leptin was estimated by sandwich ELISA technique (DRG leptin ELISA kit, Marburg, Germany).. Both the groups were comparable for age, WHR and BMI. Serum leptin was significantly higher in patients with cancer prostate as compared to controls (median 14.18 ng/ml vs. 1.63 ng/ml; p< 0.001). The level of leptin was found to have positive correlation with BMI and WHR in controls (r=0.485, p=0.007; r=0.314, p=0.091, respectively) however, no correlation was observed in patients with cancer prostate (r=0.071, p=0.711; r=0.067, p=0.725, respectively). There was no correlation between leptin and PSA. The serum leptin level was not related to the Gleason's score and stage of the carcinoma.. This study shows that Prostate cancer is associated with raised serum leptin which is independent of obesity and serum PSA. It hints the role of leptin in pathogenesis of this tumor. It may not be a surrogate marker of aggressiveness. For validation, further studies including a large patient population is required.

Topics: Aged; Biomarkers, Tumor; Body Mass Index; Humans; India; Leptin; Male; Middle Aged; Obesity; Prostatic Neoplasms; Waist-Hip Ratio

Adiposity and adipocyte-derived cytokines have been implicated in prostate carcinogenesis. However, the relationship of adipokine gene variants with prostate cancer risk has not been thoroughly investigated. We therefore examined common variants of the IL6, LEP, LEPR, TNF and ADIPOQ genes in relation to prostate cancer in a case-control study nested within a large cohort of Finnish men. The study sample consisted of 1,053 cases of prostate cancer, diagnosed over an average 11 years of follow up, and 1,053 controls matched to the cases on age, intervention group and date of baseline blood draw. Logistic regression was used to model the relative odds of prostate cancer. We also examined genotypes in relation to serum insulin, IGF-1 and IGF-1:IGFBP-3 among 196 controls. Variant alleles at three loci (-14858A>G, -13973A>C, -13736C>A) in a potential regulatory region of the LEP gene conferred a statistically significant 20% reduced risk of prostate cancer. For example, at the -14858A>G locus, heterozygotes and homozygotes for the A allele had an odds ratio (OR) of prostate cancer of 0.76 [95% confidence interval (CI) 0.62, 0.93] and 0.79 (95% CI 0.60, 1.04), respectively. At 13288G>A, relative to the GG genotype, the AA genotype was associated with a suggestive increased risk of prostate cancer (OR = 1.29; 95% CI 0.99,1.67; p(trend) = 0.05). Polymorphisms in the IL6, LEPR, TNF and ADIPOQ genes were not associated with prostate cancer. Allelic variants in the LEP gene are related to prostate cancer risk, supporting a role for leptin in prostate carcinogenesis.

Topics: Adipokines; Adiponectin; Aged; Case-Control Studies; Cohort Studies; Cytokines; Finland; Humans; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Linkage Disequilibrium; Male; Middle Aged; Prostatic Neoplasms; Receptors, Leptin; Risk; Tumor Necrosis Factor-alpha

Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development. TRAMP mice were assigned to ad libitum (AL), ICR (2 wk 50% AL consumption followed by 2 wk pair feeding to AL consumption), and CCR (25% AL consumption) groups at 7 wk of age and followed until disease burden necessitated euthanasia or mice reached terminal endpoints (48 or 50 wk of age). Body weights fluctuated in response to calorie intake (P < 0.0001). ICR mice were older at tumor detection than AL (P = 0.0066) and CCR (P = 0.0416) mice. There was no difference for age of tumor detection between AL and CCR mice (P = 0.3960). Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups. These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.

Topics: Adiponectin; Aging; Animals; Body Composition; Caloric Restriction; Diet; Genotype; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Transgenic; Neoplasm Metastasis; Prostatic Neoplasms; Survival Rate; Time Factors

Chronic intra-prostatic inflammation and obesity are thought to influence prostate carcinogenesis. Thus, variants in genes in these pathways could be associated with prostate cancer risk.. We genotyped 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG, and TCF7L2 in 258 white prostate cancer cases and 258 matched controls nested in CLUE II. Single-locus analyses were conducted using conditional logistic regression. TagSNPs were selected in IL10, CRP, and TLR4 and haplotype analyses were done.. The A allele of IL10 -1082G>A (rs1800896), known to result in lower levels of this anti-inflammatory cytokine, was positively associated with risk (AG vs. GG, OR = 1.69, 95% CI: 1.10-2.60; AA vs. GG, OR = 1.81, 95% CI: 1.11-2.96; P (trend) = 0.02). Associations of IL10 haplotypes with prostate cancer were explained by high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and -1082G>A. A TLR4 candidate SNP (rs4986790; AG/GG vs. AA, OR = 0.60, 95% CI: 0.33-1.08; P(trend) = 0.09), known to have decreased expression and be associated with lower circulating levels of inflammatory mediators, and tagSNP (rs10116253; CC vs. TT, OR = 3.05, 95% CI: 1.11-8.41), but not haplotypes, were associated with risk. None of the other candidate SNPs or haplotypes was statistically significantly associated with risk.. Our prospective study suggests that genetic variation in IL10 and possibly TLR4 is associated with prostate cancer risk. Although none of the SNPs in the obesity genes tested was associated, this does not rule out a complex role of obesity and its metabolic consequences in prostate cancer etiology.

Topics: Adult; C-Reactive Protein; Case-Control Studies; Cohort Studies; Endoribonucleases; Exons; Female; Genetic Variation; Humans; Interleukin-10; Interleukins; Introns; Leptin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; PPAR gamma; Promoter Regions, Genetic; Prospective Studies; Prostatic Neoplasms; Toll-Like Receptor 4

We estimated the circulating levels of adipocytokines such as adiponectin and leptin in nonobese nondiabetic prostate cancer (PCa) patients and compared the results with controls and benign prostate hyperplasia (BPH) patients.. Fifty patients with PCa, 20 patients with BPH and 50 healthy volunteers were entered into the study. Their blood samples were investigated for adipocytokines with the ELISA method.. Adiponectin levels were determined as 8.9 and 5.5 microg/ml for the same patients. Leptin concentration was 14.78 ng/ml in organ-confined PCa patients, and 15.24 ng/ml in advanced PCa patients. In control patients, adiponectin and leptin levels were 18.4 and 12.98 ng/ml, respectively.. Serum adipocytokine levels of PCa patients were significantly different from those of controls and BPH patients who were not obese or diabetic. Therefore, further molecular investigation of these adipocytokines will help understand the mechanism.

Topics: Adiponectin; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms

Recent epidemiologic studies have identified obesity as a risk factor for benign prostatic hyperplasia (BPH). We examined whether adiponectin, leptin, and C-peptide were associated with incident, symptomatic BPH and whether these factors mediate the relationship between obesity and BPH risk.. Data are from Prostate Cancer Prevention Trial placebo arm participants who were free of BPH at baseline. Incident BPH (n = 698) was defined as treatment, two International Prostate Symptom Score (IPSS) values > 14, or an increase of >or=5 in IPSS from baseline documented on at least two occasions plus at least one score >or=12. Controls (n = 709) were selected from men reporting no BPH treatment or IPSS > 7 during the 7-year trial. Baseline serum was analyzed for adiponectin, C-peptide, and leptin concentrations.. Neither C-peptide nor leptin was associated with BPH risk. The odds ratio [95% CI] contrasting highest to lowest quartiles of adiponectin was 0.65[0.47, 0.87] P(trend) = 0.004. Findings differed between levels of physical activity: there was a strong inverse association between adiponectin and BPH among moderately/very active men OR = 0.43 [0.29, 0.63], and no association among sedentary/minimally active men OR = 0.92 [0.65, 1.30] P(interaction) = 0.005. Adiponectin concentrations explained only a moderate amount of the relationship between obesity and BPH risk.. High adiponectin concentrations were associated with reduced risk of incident, symptomatic BPH. This association was limited to moderately/very active men; suggesting the relationship between obesity and BPH involves a complex interaction between factors affecting glucose uptake and insulin sensitivity. However, adiponectin is likely not the only mechanism through which obesity affects BPH risk.

Topics: Adiponectin; Aged; C-Peptide; Case-Control Studies; Disease Progression; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Prostatic Hyperplasia; Prostatic Neoplasms; Risk Factors; Washington

We hypothesize that adiponectin and leptin may be capable of mediating some of the effects that body weight has on prostate cancer and that a mouse model may be effective to examine this hypothesis. We found that tumors from the TRAMP prostate cancer model expressed adiponectin and leptin receptors. TRAMP-C2 prostate cancer cell proliferation was reduced by adiponectin. Leptin was able to block the ability of adiponectin to reduce cell proliferation through altered signaling of the ERK pathway. Overall, this work suggests that adiponectin, leptin, and their receptors may play an important role in prostate cancer.

Topics: Adiponectin; Animals; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Leptin; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Receptors, Adiponectin; Receptors, Leptin; Signal Transduction

Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP) cells as well as androgen-insensitive (PC-3 and DU-145) cells. At a concentration of 200 nm, LNCaP cells showed a significant increase (20% above control; P < .0001) in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P < .01 to P < .0001) dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity.

Topics: Androgens; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Leptin; Male; MAP Kinase Signaling System; Neoplasm Invasiveness; Prostatic Neoplasms

Obesity is associated with advanced prostate cancer. Here we demonstrate that in mouse prostate cancer TRAMP-C1 cells epididymal fat extracts from high-fat diet-fed obese mice stimulate androgen-independent cell growth more significantly than those from low-fat diet-fed lean mice or genetically obese leptin-deficient ob/ob mice in correlation with leptin concentrations. This result suggests that obesity promotes androgen-independent prostate cancer cell growth via adipose leptin. We have reported that added leptin stimulates androgen-independent prostate cancer cell proliferation through c-Jun NH(2)-terminal kinase (JNK). As with JNK, signal transducer and activator of transcription 3 (STAT3) and Akt are implicated in androgen-independent prostate cancer. In this study, we identify novel interaction of these three molecules in leptin-stimulated androgen-independent cell proliferation. Leptin activates JNK, STAT3 and Akt in a biphasic manner with a similar time-course. Pharmacological JNK inhibition suppresses leptin-stimulated DNA binding activity, as well as Ser-727 phosphorylation, of STAT3. Since JNK upregulates STAT3 activity via Ser-727 phosphorylation, JNK mediates leptin-stimulated STAT3 activation through Ser-727 phosphorylation. Moreover, JNK inhibition impairs leptin-stimulated Ser-473 phosphorylation of Akt that is required for its activation. Thus, JNK is involved in leptin-stimulated Akt activation. These findings together indicate that JNK mediates leptin-stimulated androgen-independent prostate cancer cell proliferation via STAT3 and Akt.

Topics: Adipose Tissue, White; Animals; Antibodies; Cell Line, Tumor; Cell Proliferation; DNA; Enzyme Inhibitors; Gene Expression; Humans; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Biological; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Prostatic Neoplasms; Protein Binding; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Tissue Extracts

To evaluate the expression of leptin and leptin receptor in benign prostatic hyperplasia (BPH) and prostate cancer (PCa), and to investigate whether they are associated with the development and progression of PCa.. Immunohistochemical staining was performed to examine the expression of leptin and leptin receptor in BPH and PCa. PCa was divided into three groups: localized PCa, locally advanced PCa and metastatic PCa. The positive staining was identified and the percentage of the positive staining was graded. We also assessed the relationship between both the Gleason score and body mass index (BMI) and PCa.. The percentage of the leptin expression in PCa was significantly higher than that in BPH (P < 0.01). For the PCa group, the expressed levels of leptin showed a considerable correlation with localized PCa and metastatic PCa (P < 0.05). Leptin receptor, however, did not reveal a definite difference between BPH and PCa. The expression of leptin indicated a significant difference between well-differentiated PCa (Gleason score =or< 6) and poorly differentiated PCa (Gleason score 8?0) (P < 0.05). The relation between the leptin expression level in PCa and the BMI was not remarkable (P = 0.447).. Our results suggest that leptin might have a promoting effect on the carcinogenesis and progression of PCa.

Topics: Aged; Biomarkers; Body Mass Index; Disease Progression; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Neoplasm Metastasis; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Leptin

Prior studies report slightly lower prostate-specific antigen (PSA) levels among obese men. To understand this effect, we investigated the association between PSA and blood HbA1c, C-peptide, leptin and adiponectin levels in African-American (AA) (n=121) and Caucasian (CA) (n=121) men. Among AA men, PSA levels decreased with increasing C-peptide levels (PSA=0.99, 0.93, 0.75 and 0.53 ng ml(-1) across quartiles of C-peptide, respectively; P(trend)=0.005). Among CA men, PSA levels decreased with increasing HbA1c (PSA=0.84, 0.73, 0.77 and 0.45 ng ml(-1) across quartiles of HbA1c, respectively; P(trend)=0.005). This may suggest that metabolic disturbances related to metabolic syndrome or diabetes affect the ability to detect early-stage prostate cancer.

Topics: Adiponectin; Adult; Aged; Black or African American; Body Mass Index; C-Peptide; Cohort Studies; Diabetes Complications; Early Diagnosis; Glycated Hemoglobin; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; White People

To investigate the effects of leptin, full-length adiponectin (fAd) and globular adiponectin (gAd), alone and in combination, on LNCaP and PC3 prostate cancer cell proliferation, and on the expression of p53 and bcl-2 gene expression.. LNCaP and PC3 prostate cancer cells were cultured and treated with the following: 0-100 nM leptin; 0-100 nM fAd +/- 100 nM leptin; 0-100 nM gAd +/- 100 nM leptin. Proliferation assays and quantitative reverse transcriptase-polymerase chain reaction for p53 tumour-suppressor gene and bcl-2 oncogene expression were performed on treated samples.. Co-incubation of PC3 cells with 100 nM leptin and 1 or 100 nM fAd significantly decreased cell proliferation to approximately half of basal (P < 0.001); there was no significant effect in LNCaP cells. Leptin-induced inhibition of p53 expression in LNCaP cells was rescued by fAd. Leptin and fAd dose-dependently potentiated p53 expression in PC3 cells (P < 0.001); leptin and gAd also increased p53 expression (P < 0.05 and P < 0.001). fAd and gAd had no effect on bcl-2 expression in the presence of leptin in LNCaP cells. In PC3 cells, bcl-2 expression was inhibited to negligible levels in the presence of leptin.. Leptin and adiponectin interact, resulting in the inhibition of prostate cancer cell proliferation, particularly in PC3 cells, via modulation of p53 and bcl-2 expression. Our findings support the notion that high leptin and low adiponectin levels may be important in driving obesity-related prostate cancer progression.

Topics: Adiponectin; Cell Line, Tumor; Cell Proliferation; Humans; Leptin; Male; Obesity; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

To investigate the proliferative and anti-apoptotic effects of leptin on human prostate cancer cells, and the role of related signalling pathways in mediating these actions, as obesity is a possible risk factor for prostate cancer and leptin, an adipocyte-derived hormone, has mitogenic action in various cell types.. Two human prostate cancer cell lines, DU145 and PC-3, were treated with leptin (5-100 ng/mL) for up to 48 h. Under serum-free conditions, cell proliferation was measured using a colorimetric tetrazolium assay and apoptosis by an enzyme-linked immunosorbent assay measuring cell death. Also, the phosphorylation of ERK1/2 and Akt was detected by Western blotting, and specific inhibitors of mitogen-activated protein kinase (MAPK) (PD98059; 40 microm) and phosphatidylinositol 3-kinase (PI3-K, LY294002; 40 microm) were used to evaluate the role of these signalling pathways.. Leptin dose-dependently increased the cell number in both cell lines for up to 48 h of incubation, the mean (sem) percentage of the control being 189 (4.3)% for DU145 and 173 (7.5)% for PC-3 (100 ng/mL leptin, 48 h; P < 0.01). Leptin also significantly reduced the number of apoptotic cells after 24 h of treatment, dose-dependently caused ERK1/2 and Akt phosphorylation; pretreatment with inhibitors of MAPK and PI3-K inhibited these responses.. These results show that chronic increases in leptin might enhance the growth of prostate cancer via the MAPK and PI3-K pathways. Further studies are needed to investigate whether the ability of leptin to stimulate mitogenic/anti-apoptotic signal transduction pathways could represent a target for anticancer drug discovery.

Topics: Adipocytes; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Leptin; Male; Mitogen-Activated Protein Kinases; Obesity; Phosphatidylinositol 3-Kinases; Phosphorylation; Prostatic Neoplasms; Risk Factors; Signal Transduction

Calorie restriction can inhibit or delay carcinogenesis, reportedly due to a reduction in calorie intake rather than by concurrent changes in body mass and/or composition. Our objective was to test the hypothesis that body mass and/or composition have an important effect, independent of energy intake, on the benefits or hazards associated with calorie restriction or overeating, respectively. In the first experiment, transgenic mice that spontaneously develop prostate cancer [transgenic adenocarcinoma of mouse prostate (TRAMP)] were housed at 27 degrees C or 22 degrees C and pair fed the same diet for 21 weeks (95% of ad libitum intake at 27 degrees C). In the second experiment, TRAMP mice were housed at 27 degrees C or 22 degrees C and fed the same diet ad libitum for 21 weeks. Despite a similar calorie intake, pair-fed mice at 27 degrees C (PF27) were heavier (28.3 +/- 3.3 versus 17.6 +/- 1.6 g at 21 weeks; P < 0.001; mean +/- SD) and had greater fat (6.4 +/- 2.1 versus 1.9 +/- 0.3 g; P < 0.001) and lean mass (P < 0.001) than pair-fed mice at 22 degrees C. Furthermore, PF27 mice had greater levels of serum leptin (P < 0.001), lower levels of adiponectin (P < 0.05), and a greater frequency of prostatic adenocarcinoma (P < 0.05). In contrast, ad libitum-fed mice housed at 22 degrees C consumed approximately 30% more calories than ad libitum-fed mice at 27 degrees C, but there was no difference between groups in body composition or cancer progression. These results imply that the ability of calorie restriction to inhibit or delay cancer incidence and progression is mediated in part by changes in energy balance, body mass, and/or body composition rather than calorie intake per se, suggesting that excess calorie retention, rather than consumption, confers cancer risk.

Topics: Adenocarcinoma; Adiponectin; Animals; Body Composition; Caloric Restriction; Disease Progression; Eating; Energy Metabolism; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organ Size; Prostatic Neoplasms; Testis; Testosterone

Factors related to insulin resistance have been implicated in prostate cancer development, however, few analytical studies support such an association. We performed a case control study on 392 prostate cancer cases and 392 matched controls nested in a prospective cohort in Northern Sweden. Plasma concentrations of C-peptide, leptin, glycated haemoglobin (HbA1c) and fasting and post-load glucose were analysed and homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Conditional logistic regression analyses were used to calculate odds ratios (OR) of prostate cancer. High levels of C-peptide, HOMA-IR, leptin and HbA1c were associated with significant decreases in risk of prostate cancer, with ORs for top vs. bottom quartile for C-peptide of 0.59 (95% Confidence Interval [CI], 0.40-0.89; p(trend) = 0.008), HOMA-IR 0.60 (95% CI, 0.38-0.94; p(trend) = 0.03), leptin 0.55 (95% CI, 0.36-0.84; p(trend) = 0.006) and HbA1c 0.56 (95% CI, 0.35-0.91; p(trend) = 0.02). All studied factors were strongly inversely related to risk among men less than 59 years of age at blood sampling, but not among older men, with a significant heterogeneity between the groups for leptin (p(heterogeneity) = 0.006) and fasting glucose (p(heterogeneity) = 0.03). C-peptide and HOMA-IR were strongly inversely related to non-aggressive cancer but were non-significantly positively related to risk of aggressive disease (p(heterogeneity) = 0.007 and 0.01, respectively). Our data suggest that androgens, which are inversely associated with insulin resistance, are important in the early prostate cancer development, whereas insulin resistance related factors may be important for tumour progression.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Case-Control Studies; Fasting; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Logistic Models; Lymphatic Metastasis; Male; Odds Ratio; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Sweden

Topics: Adipocytes; Adiponectin; Apoptosis; Bone Marrow Cells; Cell Movement; Disease Progression; Humans; Leptin; Lipid Metabolism; Male; Prostatic Neoplasms

The prevalence of metabolic syndrome is high and is increasing in parallel with increasing incidences of breast and prostate cancers. The combination of soy with tea was shown to have synergistic effects on preventing breast and prostate tumors, but the effects of soy and tea combinations on metabolic syndrome-related elements have not been investigated.. We aimed to determine the effects of soy and tea components, alone and in combination, on abdominal adipose mass and serum concentrations of adipokines, growth factors, and sex hormones in male and female mice.. Male and female FVB/N mice were treated with soy, tea components, or both. Food intake and body weight were monitored weekly. At the end of the experiment, abdominal white adipose tissue was weighed, and serum concentrations of biomarkers were measured.. Whole teas, but not the tea polyphenol extracts, significantly reduced abdominal white adipose tissue by 43-60% in female mice and by 65-70% in male mice. The combination of soy phytochemical concentrate and green tea reduced serum insulin-like growth factor-I concentrations in both male and female mice in a synergistic manner. The soy phytochemical concentrate and tea combinations reduced serum estrogen concentrations in female mice in a synergistic manner. Soy phytochemical concentrate and teas also significantly reduced serum leptin concentrations in both male and female mice and testosterone concentrations in male mice.. Further research is warranted to investigate whether soy and tea combinations may prevent breast or prostate cancer in a synergistic manner in part by alleviating metabolic disorders.

Topics: Abdominal Fat; Adiponectin; Animals; Breast Neoplasms; Diet; Drug Synergism; Estrogens; Female; Humans; Insulin-Like Growth Factor I; Leptin; Male; Metabolic Syndrome; Mice; Prostatic Neoplasms; Random Allocation; Soybean Proteins; Tea; Testosterone

Androgen deprivation therapy (ADT) for prostate cancer is now used in earlier disease stages and as adjuvant treatment. Recognizing and reducing the toxicity of this therapy, including worsened lipid levels and cardiovascular disease (CVD) risks, has become an important clinical concern. Oral estrogen therapy induces hypogonadism and mitigates many side effects of ADT, but has a high thrombosis risk. Transdermal estrogen therapy (TDE) has a lower thrombosis risk than oral estrogen and may improve CVD risk compared with ADT. This prospective pilot study of 18 men with androgen-independent prostate cancer receiving ADT measured effects of TDE on lipid and inflammatory CVD risk factors before and after 8 weeks of TDE (estradiol 0.6 mg/day). During treatment, estradiol levels rose 17-fold; total cholesterol, LDL cholesterol, and apolipoprotein B levels decreased. HDL2 cholesterol increased, with no changes in triglyceride or VLDL cholesterol levels. Dense LDL cholesterol decreased and LDL buoyancy increased in association with a decrease in HL activity. Highly sensitive C-reactive protein levels and other inflammatory markers did not worsen. Compared with ADT, short-term TDE therapy of prostate cancer improves lipid levels without deterioration of CVD-associated inflammatory markers and may, on longer-term follow-up, improve CVD and mortality rates.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Apolipoproteins B; Body Composition; C-Reactive Protein; Cholesterol; Estradiol; Estrogens; Humans; Inflammation Mediators; Interleukin-6; Leptin; Lipase; Lipid Metabolism; Lipids; Lipoprotein Lipase; Lipoproteins; Male; Middle Aged; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Testosterone; Triglycerides; Tumor Necrosis Factor-alpha

The purpose of this investigation was to examine the association of obesity and the adipokines leptin, adiponectin, and interleukin-6 (IL-6) with prostate cancer risk and aggressiveness.. One hundred twenty-five incident prostate cancer cases and 125 age-matched controls were sampled from among participants in the original San Antonio Center for Biomarkers of Risk of Prostate Cancer cohort study. The odds ratios (OR) of prostate cancer and high-grade disease (Gleason sum >7) associated with the WHO categories of body mass index (kg/m(2)) and with tertiles of serum concentrations of adiponectin, leptin, and IL-6 were estimated using multivariable conditional logistic regression models.. Body mass index was not associated with either incident prostate cancer [obese versus normal; OR, 0.75; 95% confidence interval (95% CI), 0.38-1.48; P(trend) = 0.27] or high-grade versus low-grade disease (OR, 1.17; 95% CI, 0.39-3.52; P(trend) = 0.62). Moreover, none of the three adipokines was statistically significant associated with prostate cancer risk or high-grade disease, respectively: leptin (highest versus lowest tertile; OR, 0.77; 95% CI, 0.28-1.37; P(trend) = 0.57; OR, 1.20; 95% CI, 0.48-3.01; P(trend) = 0.85); adiponectin (OR, 0.87; 95% CI, 0.46-1.65; P(trend) = 0.24; OR, 1.93; 95% CI, 0.74-5.10; P(trend) = 0.85); IL-6 (OR, 0.84; 95% CI, 0.46-1.53; P(trend) = 0.98; OR, 0.84; 95% CI, 0.30-2.33; P(trend) = 0.17).. Findings from this nested case-control study of men routinely screened for prostate cancer and who had a high prevalence of overweight and obesity do not provide evidence to support that prediagnostic obesity or factors elaborated by fat cells strongly influence prostate cancer risk or aggressiveness. However, due to the small sample population, a small or modest effect of obesity and adipokines on these outcomes cannot be excluded.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cohort Studies; Humans; Interleukin-6; Leptin; Male; Middle Aged; Neoplasm Staging; Obesity; Odds Ratio; Prospective Studies; Prostatic Neoplasms; Risk Factors

Obesity has been associated with a higher risk of progression following radical prostatectomy (RP). Obese men have higher serum leptin, a hormone produced by adipocytes, which has also been shown to be an in vitro prostate cancer growth factor. We examined whether serum leptin correlates with advanced pathological findings at RP.. Preoperative serum from 225 men treated with RP between 1998 and 1999 was examined for serum leptin. Multivariate logistic regression analysis was used to determine whether serum leptin was predictive of extraprostatic extension (pT3a).. Serum leptin highly correlated with body mass index (Spearman r = 0.602, p <0.001). Serum leptin was not associated with total or percent free prostate specific antigen (PSA), biopsy or prostatectomy Gleason score, age or height. On multivariate analysis with total and percent free PSA, clinical stage, age, biopsy Gleason score, body mass index, serum leptin, and height as variables considered for entry into the model, serum PSA (p = 0.009), clinical stage (p = 0.019) and serum percent free PSA (p = 0.041) were the only variables predictive of extraprostatic extension. Serum leptin was not significantly associated with pathological stage (pT3a).. In the current study of predominantly white men with mainly low risk disease there was no statistically significant association between serum leptin and pathological stage (pT3a) at RP. In this cohort serum leptin was not a good biomarker for predicting advanced stage at RP.

Topics: Humans; Leptin; Male; Middle Aged; Multivariate Analysis; Prostatectomy; Prostatic Neoplasms

Adiponectin is a polypeptide hormone produced by adipocytes that has anti-angiogenic properties. Circulating adiponectin is lower in obese men. Obesity has been associated with advanced stage and a higher risk of biochemical progression following radical prostatectomy (RP) in several series. We examined whether serum adiponectin is associated with advanced disease stage at RP.. Adiponectin was measured by enzyme-linked immunosorbent assay in the preoperative serum of 236 men treated with RP between 1998 and 1999. The odds ratio (OR) of advanced stage (pT3a or greater) and high grade disease (pathological Gleason sum 7 or greater) associated with quartiles of adiponectin were estimated using multivariate logistic regression models.. Serum adiponectin weakly correlated inversely with body mass index (Spearman r = -0.22, p = 0.01). Serum adiponectin was not associated with cancer stage or grade. However, in normal weight men adiponectin was positively associated with high stage disease (OR 1.14, 95% CI 1.02 to 1.29, p = 0.03), although there was no statistically significant association with high grade disease (OR 1.05, 95% CI 0.94 to 1.18, p = 0.38). In overweight and obese men adiponectin was inversely associated with high grade disease (OR 0.94, 95% CI 0.87 to 1.01, p = 0.09), although there was no statistically significant association with high stage disease (OR 0.97, 95% CI 0.91 to 1.04, p = 0.43). Further adjustments for body mass index had little impact on any ORs.. These data provide evidence to suggest that adiponectin may be related to prostate cancer aggressiveness, although the direction of the associations may depend on the extent of adiposity and on cancer grade.

Topics: Adiponectin; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Logistic Models; Male; Middle Aged; Obesity; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Leptin has been consistently associated with angiogenesis and tumoral growth. A G/A single nucleotide polymorphism (SNP) at the -2548 site in leptin gene (LEP) is associated with overexpression of leptin (A-allele).. We evaluated DNA samples from 268 (536 alleles) unrelated individuals, 118 healthy controls (HCs) and 150 prostate cancer (PC) patients, for leptin gene (LEP) locus -2548 genotypes.. We found an overrepresentation of the A-allele in PC patients and that there is a significantly higher risk for PC among A carriers (OR = 1.60; confidence interval (CI), 1.13-2.28, P = 0.008). Linear trend analysis showed that quantitative increase of A-allele presence was associated with significantly higher risk for PC (P = 0.003) in heterozygous (OR = 2.11; CI, 1.20-3.71) and homozygous (OR = 2.93; CI, 1.27-6.75) genotypes. Furthermore, the AA and AG genotypes represent significantly higher risk (OR = 4.67; CI, 1.69-12.88 and OR = 2.58; CI, 1.19-5.58, respectively) for advanced disease.. According to our results we hypothesize that the polymorphism in LEP gene may be relevant to PC risk and progression, supporting the hypothesis for leptin involvement in cancer ethiopathogenesis.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Disease Progression; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Male; Middle Aged; Polymorphism, Genetic; Prostatic Neoplasms; Risk Assessment

Obesity is considered a risk for many cancers. Serum leptin levels are often elevated in obese people. Leptin acts as a mitogenic agent in many tissues; therefore, it may act to promote cancer cell growth. We previously demonstrated that leptin acts as a growth factor for prostate cancer cells in vitro. The purpose of this study was to characterize leptin receptor isoform mRNA expression in leptin-treated DU145 and PC-3 prostate cancer cell lines. Expression levels of SOCS-3, a known leptin-inducible suppressor of leptin signaling, and known mitogenic signaling pathways of PI3K and ERK were also analyzed. DU145 and PC-3 cells were treated with 0, 4, 40, or 80 ng/ml leptin for 0, 0.5, 1, 2, 4, 24, or 48 h. Multiplex RT-PCR was performed to determine mRNA levels of the short (huOB-Ra) or the long (huOB-Rb) OB-R isoforms or SOCS-3. p-Akt and p-ERK were determined by Western blot. Cell viability and apoptosis were determined by MTT and nucleosomal fragmentation assay. DU145 and PC-3 expressed huOB-Ra, huOB-Rb, and SOCS-3 mRNA. huOB-Ra mRNA levels increased in PC-3 at 48 h (P < 0.01); however, no significant changes were observed in DU145. huOB-Rb mRNA levels decreased at 48 h in DU145; however, a twofold increase at 48 h (P < 0.01) was observed with PC-3 and was dose-dependent (P < 0.05). Leptin increased SOCS-3 mRNA in DU145 at 24 and 48 h (P < 0.05) and in PC-3 at 1 h (2-fold) and 48 h (fivefold; P < 0.01). Leptin up-regulated p-Akt in a time- and dose-dependent manner in the DU145 prostate cancer cells via a suppression of apoptosis. Leptin up-regulated p-ERK in a time-dependent manner in PC-3 cells. In prostate cancer cells, the mitogenic effects of leptin are not a consequence of altered receptor isoform mRNA expression. No defect in SOCS-3 signaling was observed, and proliferation appears to be working through the PI3K and MAPK leptin receptor-activated pathways, depending on cell type. Leptin stimulation may be selective for either pathway to suppress apoptosis, thereby enhancing prostate cancer growth.

Topics: Apoptosis; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Activation; Humans; Leptin; Male; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

The adipocyte hormone leptin has been shown to increase migration and angiogenesis in epithelial cells. Therefore, we hypothesized that leptin would induce prostate cancer cell migration and growth factor expression in vitro.. Prostate cancer cell lines DU145 and PC-3 (androgen-resistant) were treated with leptin over time. Supernatants were assayed for growth factor expression via enzyme-linked immunosorbent assay (ELISA). Becton Dickinson-Falcon Transwell systems were used to assay leptin-induced migration.. Leptin significantly induced expression of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), and basic fibroblast growth factor (bFGF) in DU145 and PC-3 cells. Prostate cancer cell migration was enhanced by leptin and inhibited 50% to 70% with the addition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) inhibitors.. The mitogenic effects of leptin on cancer cells, in combination with the increased migration and expression of growth factors, overall likely contributes to the progression of prostate cancer. Therefore, obesity associated with high leptin levels should be considered a risk factor in prostate cancer patients.

Topics: Apoptosis; Cell Movement; Cell Proliferation; Humans; Leptin; Male; Neovascularization, Pathologic; Probability; Prostatic Neoplasms; Reference Values; Sensitivity and Specificity; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Several studies have shown a positive association of dietary fat with prostate cancer. Leptin, a peptide hormone that has a role in the regulation of body weight, currently serves as a more accurate biomarker for total body fat. We designed a study to determine whether leptin influences cellular differentiation and the progression of prostate cancer.. In this study we investigated serum leptin in 21 patients with prostate cancer, 50 with benign prostatic obstruction and 50 healthy individuals matched for sex, body mass index and age. Patients with cancer were stratified into 2 groups by the disease spread, including groups 1--organ confined and 2--advanced disease, and into 3 groups by the differentiation degree, including groups 3--Gleason sum 2 to 4 or well differentiated, 4--Gleason sum 5 to 7 or moderately differentiated and 5--Gleason sum 8 to 10 or poorly differentiated.. We noted significant differences in serum leptin in the cancer versus control and cancer versus benign prostatic obstruction groups. In addition, in the prostate cancer group serum leptin correlated with prostate specific antigen and biopsy Gleason score. We also observed significant differences in serum leptin in groups 1 versus 2, 3 versus 5 and 4 versus 5.. Leptin may have roles in the development of prostate cancer through testosterone and factors related to obesity. It influences cellular differentiation and the progression of prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Body Weight; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Risk Factors; Testosterone; Urinary Bladder Neck Obstruction

Topics: Case-Control Studies; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Prostatic Neoplasms

Despite strong indirect evidence that androgens stimulate prostate cancer development, data from most analytical studies on this association have been negative. To further investigate this issue, we studied the interrelationships between androgenicity and insulin-like growth factor I (IGF-I), insulin and leptin. Within a prospective cohort study, we measured testosterone, sex hormone-binding globulin (SHBG) and IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, insulin and leptin, in plasma from 149 cases and 298 controls. Testosterone correlated positively with SHBG, whereas testosterone and SHBG correlated inversely with IGF-I, IGFBP-3, insulin, leptin and body mass index (BMI). Indices of free testosterone showed an inverse linear correlation with leptin (P<0.01), and a strong drop in the 5th quintile of BMI. However, levels of free testosterone showed non-linear relationships over quintiles of insulin and IGF-I, with a significant increase in the second quintile of IGF-I compared with other levels. The absence of an association between plasma levels of androgens and prostate cancer risk in analytical studies, despite the strong indirect evidence of their tumour-stimulating effects, may reflect the complex and mostly inverse associations of androgenicity to IGF-I, insulin and leptin which are hormones that have also been implicated as risk factors for prostate cancer.

Topics: Body Mass Index; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Prospective Studies; Prostatic Neoplasms; Risk Factors; Sex Hormone-Binding Globulin; Sweden; Testosterone

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgen-independent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.

Topics: Adipocytes; Cell Division; Cell Line, Tumor; Cells, Cultured; Cytokines; Drug Synergism; Enzyme Inhibitors; Humans; Insulin-Like Growth Factor I; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mitogen-Activated Protein Kinases; Obesity; Paracrine Communication; Prostatic Neoplasms

Leptin, a protein produced by adipocytes, is an important signaling molecule in energy regulation and food intake. Many obese patients have leptin resistance associated with increased circulating leptin. Leptin receptor activation downregulates many regulatory genes, including STAT-3 and PAP 1. Certain cancers are associated with obesity, including breast, prostate, and colon. Recent studies have shown that leptin stimulates proliferation of human colon cancer in vitro. We hypothesized that leptin would have stimulatory effects on other human cancers.. Human cancer cell lines from esophagus (KYSE410 and 150), breast (ZR75-1 and MCF-7), prostate (DU145 and PC-3), and pancreas (PANC-1, Mia-PaCa) were cultured using standard techniques. Leptin (0.4 ng/ml and 4.0 ng/ml) was added for 24 h and 48 h. Cell growth was determined by MTT assay. Statistical analysis was performed using analysis of variance.. Cancer cell lines demonstrated dose- and time-related responses to treatment. Leptin caused growth potentiation in breast, esophagus, and prostate cancer (P < 0.05). However, in both Mia-PaCa and PANC-1 pancreatic cancer cells, leptin inhibited growth (P < 0.05). This inhibitory effect peaked in PANC-1 at 48 h (78%).. We have shown for the first time that human cancer cells exhibit differential responses to treatment with leptin, depending upon organ of derivation. Both leptin and leptin antagonism have potential efficacy in cancer therapy, based on cellular origin. Further studies are warranted and ongoing.

Topics: Breast Neoplasms; Cell Division; Esophageal Neoplasms; Female; Humans; Leptin; Male; Neoplastic Processes; Pancreatic Neoplasms; Pancreatitis-Associated Proteins; Peptide Hormones; Prostatic Neoplasms; Tumor Cells, Cultured

Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition).. In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors 0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases ("high-volume disease"), matched by age (+/- 5 years) and year at diagnosis (+/- 1 year).. Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) = 2.35, 95% confidence interval (CI) = 1.01-5.44), as did men with high leptin and high testosterone (OR = 9.73, 95% CI = 2.05-46.24) and men >/=5'8" with high leptin (OR = 3.67, 95% CI = 1.40-9.63).. Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity.

Topics: Aged; Body Height; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Humans; Leptin; Logistic Models; Male; Middle Aged; Multivariate Analysis; Prostatic Neoplasms; Radioimmunoassay; Regression Analysis; Statistics, Nonparametric; Testosterone; White People

Cachexia is rarely observed in patients with advanced prostate cancer treated with combined androgen blockade. Androgens play an important role in the regulation of body mass composition and influence the secretion of leptin, the appetite regulating hormone. The aim of the study was to assess the influence of a combined treatment with nonsteroidal antiandrogen and LH-RH analogue on the hormonal regulation of appetite and changes in body mass in patients with advanced prostate cancer (Whitmore-Jewett stage D1 or D2). Eighteen patients with prostate cancer and 17 healthy subjects matched for age and body mass index were included. In all patients serum concentrations of leptin, neuropeptide Y (NPY), insulin, testosterone and estradiol were measured before and after four and twelve weeks of androgen blockade. Pretreatment serum leptin levels were similar in patients with prostate cancer and in the controls. In a multiple regression analysis only body mass index and testosterone significantly contributed to the variation of plasma leptin. During the treatment body mass and plasma leptin significantly increased while NPY decreased. The change of plasma NPY was significant only after 4 weeks of therapy. This study shows that the afferent regulation of leptin secretion is unchanged in advanced prostate cancer. Androgen ablation significantly increases body mass and influences secretion of appetite regulating hormones. Testosterone appears to play a significant role in the regulation of leptin secretion.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Appetite; Body Constitution; Body Mass Index; Body Weight; Estradiol; Flutamide; Goserelin; Humans; Insulin; Leptin; Male; Middle Aged; Neuropeptide Y; Prostatic Neoplasms; Regression Analysis; Testosterone

A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1-3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk.

Topics: Adult; Aged; Blood Pressure; Body Mass Index; Carrier Proteins; Epithelium; Female; Health Surveys; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Logistic Models; Male; Middle Aged; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Receptors, Cell Surface; Receptors, Leptin; Risk Factors; Sex Hormone-Binding Globulin; Smoking; Sweden; Testosterone

In a previous study of Chinese men, we found that men with a higher waist-to-hip ratio (WHR) have a higher prostate cancer risk. Because leptin and insulin are related to body fat distribution, we examined whether leptin and insulin were associated with prostate cancer risk.. Blood samples were collected from 128 case patients with incident prostate cancer and from 306 healthy control subjects randomly selected from residents of Shanghai, CHINA: Epidemiologic information and anthropometric measurements were collected in personal interviews. Serum leptin, insulin, and sex hormone levels were measured by radioimmunoassay, and insulin-like growth factor-I (IGF-I) was measured by enzyme-linked immunosorbent assay. Multiple logistic regression analyses were used to estimate odds ratios for prostate cancer in relation to serum insulin and leptin levels. All statistical tests were two-sided.. After adjustment for body mass index, WHR, IGF-I, and sex hormone levels, higher serum insulin levels were associated with a statistically significantly elevated risk of prostate cancer (P<.001). Men in the highest tertile of insulin levels had a 2.56-fold (95% confidence interval [CI] = 1.38 to 4.75) risk of prostate cancer compared with men in the lowest tertile. Regardless of the tertile level of WHR, higher serum insulin levels were associated with an increased risk of prostate cancer: Men in the highest tertiles of WHR (>0.900) and insulin (>8.83 microU/mL) had 8.55 times (95% CI = 2.80 to 26.10) the prostate cancer risk of men in the lowest tertiles of both, and those in the lowest tertile of WHR (<0.873) and highest tertile of insulin had 4.30 times (95% CI = 1.17 to 15.70) the risk. By contrast, the association between leptin levels and prostate cancer risk was not statistically significant.. Our results suggest that serum insulin levels may influence the risk of prostate cancer in Chinese men. Further research, especially prospective studies, is needed to confirm these findings in high-risk populations and to clarify the underlying mechanisms involved.

Topics: Age Factors; Aged; Case-Control Studies; China; Enzyme-Linked Immunosorbent Assay; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Odds Ratio; Prostatic Neoplasms; Radioimmunoassay; Risk Factors; Testosterone

The aim of our study was to determine whether leptin, a hormone implicated in both energy-balance and reproductive function, is involved in the etiology of prostate cancer or benign prostatic hyperplasia (BPH). We compared the serum leptin levels of 43 cases of incident prostate cancer, 41 patients with BPH, and 48 healthy controls, all recruited in Athens, Greece. Multiple logistic regression modeling was used, with adjustment for age, height, body mass index, education, estradiol, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin and insulin like growth factor 1. Odds ratios per 4 ng/ml increment of leptin were 0.70 [95% confidence interval (CI) (0.32,1.55)] for prostate cancer and 1.06 [95% CI (0.67,1.67)] for BPH. After adjustment for body mass index, serum leptin levels were not significantly correlated with levels of any of the other hormones under study. Leptin levels are unlikely to affect the risk of either prostate cancer or BPH substantially.

Topics: Aged; Humans; Leptin; Male; Prostatic Hyperplasia; Prostatic Neoplasms; Proteins