leptin and Colorectal-Neoplasms

Obesity and colorectal cancer (CRC) are among the leading diseases causing deaths in the world, showing a complex multifactorial pathology. Obesity is considered a risk factor in CRC development through inflammation, metabolic, and signaling processes. Leptin is one of the most important adipokines related to obesity and an important proinflammatory marker, mainly expressed in adipose tissue, with many genetic variation profiles, many related influencing factors, and various functions that have been ascribed but not yet fully understood and elucidated, the most important ones being related to energy metabolism, as well as endocrine and immune systems. Aberrant signaling and genetic variations of leptin are correlated with obesity and CRC, with the genetic causality showing both inherited and acquired events, in addition to lifestyle and environmental risk factors; these might also be related to specific pathogenic pathways at different time points. Moreover, mutation gain is a crucial factor enabling the genetic process of CRC. Currently, the inconsistent and insufficient data related to leptin's relationship with obesity and CRC indicate the necessity of further related studies. This review summarizes the current knowledge on leptin genetics and its potential relationship with the main pathogenic pathways of obesity and CRC, in an attempt to understand the molecular mechanisms of these associations, in the context of inconsistent and contradictory data. The understanding of these mechanisms linking obesity and CRC could help to develop novel therapeutic targets and prevention strategies, resulting in a better prognosis and management of these diseases.

Topics: Adipokines; Adipose Tissue; Colorectal Neoplasms; Humans; Leptin; Obesity; Receptors, Leptin

The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC.

Topics: Adiponectin; Age of Onset; Carboxy-Lyases; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; GATA4 Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Leptin; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, Notch4

The association of adiponectin with metabolism and cancer is well established. Since its discovery in 1990, adiponectin, as one of the adipose tissue-secreted adipokines, has been very widely studied in biomedical research. Low levels of circulatory adiponectin have been reported in obesity, inflammatory diseases and various types of cancers including colorectal cancer (CRC), which is highly linked with obesity and gut inflammation. However, the function and underlying mechanisms of adiponectin in CRC is not well understood. In addition, there are contradictory reports on the role of adiponectin in cancer. Therefore, further investigation is needed. In this review, we explore the information available on the relationship between adiponectin and CRC with respect to proliferation, cell survival, angiogenesis and inflammation. We also highlighted the knowledge gaps, filling in which could help us better understand the function and mechanisms of adiponectin in CRC.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Leptin; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Obesity; Tumor Microenvironment

The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic, metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signalling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinaemia and hyperleptinaemia in prediabetes and excess circulating glucose and lipids in T2D overcome formidable barriers for tumour development. Increased nutrient availability favours metabolic reprogramming, alters signalling and generates mutations and epigenetic modifications through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signalling is lost in diabetes. Excess adipose tissue at the origin of T2D unbalances adipokine (leptin/adiponectin) secretion ratios and function and disrupts the insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumourigenesis. Disruption of the insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.

Topics: Adiponectin; Animals; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Humans; Insulin; Leptin

Leptin and adiponectin are adipokines which have been commonly implicated in carcinogenesis. As such, many studies have investigated the association of circulating leptin and adiponectin levels with colorectal cancer (CRC) risk. However, the results remained inconsistent.. In this work, we performed a systematic review and meta-analysis to precisely examine the association between circulating levels of leptin and adiponectin and CRC risk. A systematic literature search was performed in PubMed/MEDLINE, Scopus, Web of Science, and EMBASE databases from inception until October 2020. The pooled effect size was then estimated by calculating the odds ratio (OR).. A total of 23 records (comprising 26 studies) were included in the meta-analysis. The overall analysis found that circulating levels of leptin and adiponectin were not significantly associated with CRC risk (P > 0.05). Interestingly, subgroup analysis revealed that a higher level of adiponectin was significantly associated with an increased CRC risk among overweight individuals (OR = 1.16; 95 % CI: 1.02, 1.32), and a decreased CRC risk among normal weight individuals (OR = 0.76; 95 % CI: 0.62, 0.92). Besides, a higher level of adiponectin was also significantly associated with a decreased risk of CRC in men (OR = 0.76; 95 % CI: 0.59, 0.98).. In conclusion, circulating leptin level was not associated with CRC risk, but that of adiponectin was associated with CRC risk only in specific subgroups.

Topics: Adiponectin; Case-Control Studies; Colorectal Neoplasms; Humans; Leptin; Risk

Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer.

Topics: Adipokines; Adiponectin; Animals; Carrier Proteins; Cell Transformation, Neoplastic; Colorectal Neoplasms; Cytokines; GPI-Linked Proteins; Humans; Lectins; Leptin; Membrane Proteins; Obesity; Overweight; Receptors, Adipokine

Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression).

Topics: Adiponectin; Carcinogenesis; Chronic Disease; Colorectal Neoplasms; Cytokines; Female; Humans; Inflammation; Leptin; Male; Obesity; Reactive Oxygen Species

Leptin is a multifunctional adipose-derived cytokine that plays a critical role in bodyweight homeostasis and energy balance. Plasma level of leptin is an indicator of the amount of energy stored in adipose tissues. Recently, leptin and leptin receptor dysregulation have been reported in a variety of malignant cells including colorectal cancers (CRCs). There are growing evidence that leptin may be the link between obesity and CRC carcinogenesis. Leptin influence the growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including JAK/STAT, PI3-kinase/AKT, and/or MAP kinases. In this review, current understanding of leptin and its receptor's roles in the pathogenesis of colonogenic cancer has been described.

Topics: Adipose Tissue; Carcinogenesis; Colorectal Neoplasms; Energy Metabolism; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Leptin; Receptors, Leptin; Signal Transduction

Obesity has been considered as an important risk factor for the development of colorectal cancer (CRC), but the association has not been fully elucidated. Obesity is linked significantly to adipose tissue dysfunction and to alteration of adipokines in blood; in particular, obesity-induced inflammation is thought to be an important link between obesity and colorectal cancer. Based on epidemiological studies, we undertook a systematic review to understand the association of circulating levels of selected adipokines, including adiponectin, leptin, resistin, IL-6 and TNF-α, with the level of CRC risk. Most prospective studies suggested protective effects of adiponectin, but these were attenuated by body mass index (BMI) and waist circumference (WC) data in our meta-analysis. On the other hand, meta-analyses for leptin and CRC did not demonstrate any association, similar to the results of systematic review. Although it proved difficult to determine whether other selected adipokines (resistin, IL-6 and TNF-α) were related to CRC risk due to small number of reports, the present systematic review suggested a positive association with elevated resistin levels but null associations with IL-6 and TNF-α.

Topics: Adiponectin; Body Mass Index; Colorectal Neoplasms; Humans; Inflammation; Interleukin-6; Leptin; Obesity; Resistin; Risk Factors; Tumor Necrosis Factor-alpha; Waist Circumference

Obesity is characterized by high secretion of several cytokines from adipose tissue and is a recognized risk factor for many cancers. Among these cytokines, leptin mainly produced by adipose tissue and cancer cells is the most studied adipokine. Leptin is an activator of cell proliferation, an antiapoptotic molecule and inducer of cancer stem cells in many cell types, and its critical roles in obesity-related tumorigenesis are based on its oncogenic, mitogenic, pro-inflammatory and pro-angiogenic actions.. These leptin-induced signals and action are critical for their biological effects on energy balance, adiposity, endocrine systems, immunity, angiogenesis as well as oncogenesis. This review focuses on the up-to-date knowledge on the oncogenic role of leptin signaling, clinical significance and specific drug target development in colorectal cancer (CRC). Additionally, leptin-induced angiogenic ability and molecular mechanisms in CRC cells are discussed.. Stringent binding affinity of leptin/Ob-R and overexpression of leptin/Ob-R and their targets in cancer cells make it a unique drug target for prevention and treatment of CRC, particularly in obesity colorectal patients.

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Drug Design; Humans; Leptin; Molecular Targeted Therapy; Obesity; Risk Factors; Signal Transduction

To examine the association between obesity-related adipokines (adiponectin, leptin, resistin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and colorectal cancer (CRC) risk.. Serum levels of adipokines were measured in 100 CRC patients and age- and sex-matched controls for the data analysis. Unconditional logistic regression models were used for estimating ORs and 95%CIs related to each adipokine. For the meta-analysis, studies published before July 2013 available on Medline/PubMed and EMBASE were retrieved. The analysis included a total of 17 relevant studies (including the present case-control study): nine studies on adiponectin and eight on leptin. The effect sizes of ORs and 95%CIs were estimated using RevMan 5.1. Heterogeneity was evaluated using Cochran's Q-test and I (2) statistics.. Among the five adipokines, only resistin levels were significantly higher in cases than in controls (P < 0.001). The case-control study results showed no association between adiponectin and CRC and a negative association between leptin and CRC. However, the results of the meta-analysis showed a significant inverse association between adiponectin and CRC (OR = 0.91, 95%CI: 0.83-1.00, P = 0.04) and no association between CRC and leptin. After stratification by study design, an inverse association between adiponectin and CRC was observed in prospective studies only (OR = 0.90, 95%CI: 0.82-0.99, P = 0.03), whereas the association between leptin and CRC was inconsistent (prospective studies: OR = 1.14, 95%CI: 1.02-1.27, P = 0.02 and retrospective studies: OR = 0.47, 95%CI: 0.29-0.74, P = 0.001). The associations of resistin and TNF-α with CRC risk were positive, but no association was observed for IL-6.. Our results suggest a negative association of leptin, positive associations of resistin and TNF-α, and null associations of adiponectin and IL-6 with CRC. However, further studies with larger number of prospective approaches are needed.

Topics: Adipokines; Adiponectin; Aged; Biomarkers; Case-Control Studies; Chi-Square Distribution; Colorectal Neoplasms; Female; Humans; Interleukin-6; Leptin; Logistic Models; Male; Middle Aged; Odds Ratio; Protective Factors; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

This review will examine the recent scientific literature on the mechanisms that are thought to link obesity to colorectal cancer (CRC) risk.. Obesity has emerged as a leading environmental risk factor for the development of CRC. However, the mechanisms underlying this relationship have not yet been fully elucidated. Recent literature has focused on inflammatory processes, adipokines, and estrogen. Obesity-enhanced inflammation is largely orchestrated by increases in adipose tissue macrophages leading to the secretion of inflammatory cytokines including tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6, all of which are linked to CRC. Adiponectin is decreased with obesity and has been reported to be negatively associated with CRC, whereas leptin, which is increased, is positively associated with the disease. Estrogen has been shown to influence CRC, although its role remains controversial; some studies have implicated estrogen as being protective, whereas others have suggested it to be a risk factor. We highlight the most important recent advances that have been made on the aforementioned mechanisms that are thought to link obesity to CRC.. A better understanding of the mechanisms linking obesity to CRC risk is necessary for the design of effective treatment approaches in future clinical trials.

Topics: Adiponectin; Adipose Tissue; Chemokine CCL2; Colorectal Neoplasms; Estrogens; Humans; Inflammation; Interleukin-6; Leptin; Macrophages; Obesity; Tumor Necrosis Factor-alpha

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

Equivocal results regarding the role of leptin in colorectal cancer (CRC) and adenoma (CRA) have been reported. A case-control study investigating the association of leptin with CRC risk and clinicopathological characteristics along with meta-analysis of published data on both CRC and CRA were conducted.. Pubmed and Embase were searched for the meta-analysis, comprising 28 case-control studies amounting 3,614 CRC and 1,215 CRA cases, along with 5,220 controls. Meticulous contact with the authors of individual studies was undertaken for the provision of additional data. Pooling of standardized mean differences (SMD), relative risks (RR) and 95 % CI (random effects models), subgroup, sensitivity, and meta-regression analyses were conducted.. The meta-analysis suggested positive association of serum leptin with CRA (RR, 95 % CI 1.35, 1.03 to +1.76), but not CRC either at the pooled analysis on SMDs or RRs (SMD, 95 % CI 0.18, -0.04 to +0.40; RR, 95 % CI 1.04, 0.65 to +1.65). Significant heterogeneity between studies on CRC as well as between studies on CRA providing SMD was noted. Subgroup, meta-regression and sensitivity analyses highlighted potential methodology-, design-, size- and quality-related effect modifiers.. Meta-analysis of current evidence suggests positive association of serum leptin with CRA but not with CRC risk. Given the case-control nature of available studies, the limited number of studies on serum leptin and CRA, and the heterogeneity of CRC studies, carefully designed, prospective studies preferably reporting RRs adjusted for a variety of confounders may be warranted.

Topics: Adenoma; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Humans; Leptin; Prognosis; Risk Factors

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

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

The level of leptin in the blood shows a positive, strong correlation with the mass of adipose tissue. Being overweight and having metabolic disorders increase the risk of developing colorectal cancer.. The aim of the study was to assess the concentration of leptin in the blood serum as well as the expression of the leptin receptor in colorectal cancer cells. In addition, the effect of serum leptin concentration and leptin receptor expression on clinical and pathological parameters such as BMI, obesity, TNM, and tumor size was assessed.. The study included 61 patients diagnosed with colorectal cancer and treated with surgery.. Strong leptin receptor expression and the prevalence of overweight and obesity are factors influencing the occurrence of excessive leptin concentrations.. Leptin may be involved in the development and progression of colorectal cancer. More research is needed to better elucidate the role of leptin in the development and progression of the disease.

Topics: Body Mass Index; Colorectal Neoplasms; Humans; Leptin; Obesity; Overweight; Receptors, Leptin

Along with the rising incidence of obesity, there has been an increase in patients diagnosed with early-onset colorectal cancer (<50 years old). In colorectal cancer, worse patient survival is associated with certain cytokine expression and downregulation of peroxisome proliferator activated receptor gamma expression. The effects of the obesity hormone leptin and macrophage-specific metabolite itaconate on these mechanisms are poorly understood. We investigated their impact on peroxisome proliferator activated receptor gamma and macrophage cytokine expression in vitro.. M2-like macrophages were treated with either leptin, 4-octyl itaconate, or dimethyl itaconate in a dose- and time-dependent manner. Gene expression after treatment with 4 doses (D1-4) of each compound was analyzed at 4 time points (3, 6, 18, and 24 hours).. Peroxisome proliferator activated receptor gamma was downregulated after 4-octyl itaconate treatment at 18 hours (FC -32.67, P ≤ .001). Interleukin-8 was upregulated after leptin and dimethyl itaconate treatment at 6 hours (FC 26.35 at D4, P ≤ .001, and FC 23.26 at D3, P = .006). Dimethyl itaconate upregulated IL-1β at 24 hours (FC 18.00 at D4, P ≤ .001). Tumor necrosis factor-α showed maximum downregulation after 4-octyl itaconate at 18 hours (FC -103.25 at D4, P ≤ .001).. Itaconate downregulates peroxisome proliferator activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Itaconate provides a link between obesity and colorectal cancer and may be a key regulator in early-onset colorectal cancer.

Topics: Cell Culture Techniques; Colorectal Neoplasms; Humans; Interleukin-1beta; Interleukin-8; Leptin; PPAR gamma; Succinates; Time Factors; Tumor Necrosis Factor-alpha; Tumor-Associated Macrophages

Mechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women.. We used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis.. For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-<25 kg/m. Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity-associated cancer risk in postmenopausal women.

Topics: Adiposity; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Endometrial Neoplasms; Estradiol; Fasting; Female; Humans; Insulin; Leptin; Obesity; Postmenopause; Risk Factors

Adipocytokines have been proposed as factors mediating associations between obesity and inflammation in patients with colorectal cancer (CRC). Thus, the aim of this study was to determine the clinical relationships between blood concentrations of leptin (LEP), adiponectin (ADP), and tumor necrosis factor alpha (TNF-alpha) and the outcomes measured in patients with CRC undergoing surgery.. History, body composition, and blood concentrations of LEP, ADP, and TNF-alpha were determined in 107 patients undergoing surgery due to CRC. The patients were followed up for 619.72 ± 371.65 days.. Compared to patients with stage II CRC, individuals with clinical stage I CRC had significantly lower ADP and higher TNF-alpha blood concentrations. We found significant correlations between the clinical stage of CRC (early vs. localized vs. metastatic) and the following: crude blood ADP concentration (R = 0.25; p = 0.015), ADP-to-TNF-alpha ratio (R = 0.31; p = 0.002), and ADP when indexed to body surface area (R = 0.25; p = 0.008) and to fat mass (R = 0.25; p = 0.016). The risk of death during the long-term follow-up period was independently related to the clinical stage of CRC, impairment of the patient's functional status, and higher blood carcinoembryonic antigen concentration. In Kaplan-Meier survival analysis, patients with blood LEP concentrations adjusted to a visceral adipose tissue score of ≥0.47 had a significantly better likelihood of surviving than their counterparts.. In patients with CRC undergoing surgery, blood ADP and TNF-alpha concentrations were associated with the clinical stage of the cancer, likelihood of radical tumor excision, occurrence of nonsurgical postoperative complications, and long-term survival, which suggests the role of dysregulation in the endocrine function of adipose tissue in response to the neoplasmatic process.

Topics: Adiponectin; Adipose Tissue; Colorectal Neoplasms; Humans; Leptin; Tumor Necrosis Factor-alpha

Topics: Adipokines; Adiponectin; Body Mass Index; Carcinoma, Renal Cell; Colorectal Neoplasms; Correlation of Data; Endometrial Neoplasms; Female; Genome-Wide Association Study; Humans; Leptin; Mendelian Randomization Analysis; Obesity; Ovarian Neoplasms; Pancreatic Neoplasms; Plasminogen Activator Inhibitor 1; Principal Component Analysis; Receptors, Leptin; Risk Factors

Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma.. We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma.. Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR = 3.14, 95% CI 1.11-8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19-10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women.. In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.

Topics: Adenoma; Adipokines; Adiponectin; Aged; Biomarkers; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Risk Factors; Tumor Necrosis Factor-alpha

Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival.. We included 306 eligible incident stage II-III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models.. Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10-2.59), 2.72 (2.07-3.56), 1.97 (1.18-3.28) and 1.71 (1.14-2.58), respectively. IL-6 and adiponectin had a dose-response effect (P. Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II-III CRC patients.

Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; C-Reactive Protein; Case-Control Studies; Chemokine CCL2; Colorectal Neoplasms; Disease Progression; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Neoplasm Staging; Prognosis; Survival Analysis

Natural products are popular insights for researchers to investigate promising anti-cancer agents since some of these substances have lesser adverse effects restricting the treatment than traditional chemotherapeutic agents. A well-known monoterpene Carvacrol, widely consumed in Mediterranean cuisine and lower risks of cancer, has efficient anticancer effects. However, the mechanism of action is yet to be discovered.. The investigation aims to illuminate a new perceptive in the role of this substance on colorectal cancer treatment, by the means of differences in a well-defined range of soluble factors. Carvacrol effect on both HT-29 and HCT-116 cell lines was evaluated on proliferation and the IC50 values were calculated by the RTCA xCELLigence device. Then MAGPIX assay was performed to obtain the changes in soluble factors of the cell lines.. The Multiplexing assay suggests some of these factors were altered in favor of surviving and proliferation in aggressive cell line HCT-116 whereas they were altered against these characters in HT-29, were correlated with the increased IC50 concentration of HCT- 116 in carvacrol treatment.. The current study indicates that differences in the levels of these soluble factors could modulate the anticancer effect related to carvacrol.

Topics: Cell Proliferation; Colorectal Neoplasms; Cymenes; Granulocyte-Macrophage Colony-Stimulating Factor; HCT116 Cells; HT29 Cells; Humans; Leptin; Prolactin; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor Receptor-2

Topics: Adiponectin; Adult; Aged; Biomarkers; C-Peptide; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Insulin; Leptin; Longitudinal Studies; Male; Microsatellite Instability; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Risk Factors

Prediabetes is associated with a high risk of colon cancer, and abdominal obesity, which can result in the secretion of several obesity-related adipocytokines, is an independent influencing factor for colonic polyps in prediabetes subjects. However, the correlation between adipocytokine levels and colonic polyps in prediabetes subjects is unclear. This research explores the relationship between plasma adiponectin, visfatin, leptin, and resistin levels and the development of colonic polyps in prediabetes subjects.. A total of 468 prediabetes subjects who underwent electronic colonoscopy examinations were enrolled in this study; there were 248 cases of colonic polyps and 220 cases without colonic mucosal lesions. Then, colonic polyps patients with prediabetes were subdivided into a single-polyp group, multiple-polyps group, low-risk polyps group, or high-risk polyps group. In addition, 108 subjects with normal glucose tolerance who were frequency matched with prediabetes subjects by sex and age were selected as the control group; 46 control subjects had polyps, and 62 control subjects were polyp-free. Plasma adiponectin, visfatin, leptin, and resistin levels were measured in all the subjects, and the related risk factors of colonic polyps in prediabetes subjects were analysed.. Plasma adiponectin levels were significantly lower in the polyps group than in the polyp-free group [normal glucose tolerance (9.8 ± 4.8 vs 13.3 ± 3.9) mg/L, P = 0.013; prediabetes (5.6 ± 3.7 vs 9.2 ± 4.4) mg/L, P = 0.007]. In prediabetes subjects, plasma adiponectin levels were decreased significantly in the multiple polyps group [(4.3 ± 2.6 vs 6.7 ± 3.9) mg/L, P = 0.031] and the high-risk polyps group [(3.7 ± 2.9 vs 7.4 ± 3.5) mg/L, P < 0.001] compared to their control groups. Plasma visfatin levels were higher in the polyps group and the multiple-polyps group than those in their control groups (P = 0.041 and 0.042, respectively), and no significant difference in plasma leptin and resistin levels was observed between these three pairs of groups (all P > 0.05). The multivariate logistic regression analysis showed that lower levels of plasma adiponectin was a risk factor for colonic polyps, multiple colonic polyps, and high-risk colonic polyps in prediabetes subjects.. Plasma adiponectin levels are inversely associated with colonic polyps, multiple colonic polyps, and high-risk colonic polyps in prediabetes subjects. And adiponectin may be involved in the development of colon tumours in prediabetes subjects.

Topics: Adenomatous Polyps; Adiponectin; Adult; Aged; Case-Control Studies; China; Colonic Polyps; Colonoscopy; Colorectal Neoplasms; Cytokines; Female; Humans; Leptin; Male; Middle Aged; Neoplasms, Multiple Primary; Nicotinamide Phosphoribosyltransferase; Prediabetic State; Resistin; Risk Factors

Leptin acts as an adipocytokine functions via the leptin receptor, which stimulates growth, migration, and invasion of cancer cells. This study is aimed at identifying leptin as a prognostic factor in colorectal cancer (CRC). The differentially expressed genes with prognostic value in CRC tissues either with or without liver metastasis were assessed based on The Cancer Genomic Atlas (TCGA). Leptin was considered a candidate gene for further analysis. Its expression features of 206 CRC patients without liver metastasis and 201 patients with metastasis on tissue microarrays were assessed by immunochemical staining, and the effect of leptin on survival was assessed by Kaplan-Meier analyses. Overexpressed leptin indicated a poorer prognosis for CRC patients in overall survival (

Topics: Aged; Biomarkers, Tumor; Cohort Studies; Colon; Colorectal Neoplasms; Female; Humans; Intestinal Mucosa; Leptin; Liver; Liver Neoplasms; Male; Middle Aged; Prognosis; Treatment Outcome

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; CA-125 Antigen; Carcinoembryonic Antigen; Colorectal Neoplasms; Humans; Immunoassay; Leptin; Limit of Detection; Membrane Proteins; Surface Plasmon Resonance; Tissue Inhibitor of Metalloproteinase-1

Obesity is a major epigenetic cause for colorectal cancer (CRC). Leptin is implicated in obesity-associated CRC, but the underlying mechanism remains unclear. The current study identified over-expression of metallopanstimulin-1 (MPS-1) in CRC patients through microarray and histological analysis, especially in obese CRC patients. MPS-1 was correlated with advanced tumor stage, suggesting its association with CRC progression. In addition, MPS-1 over-expression was associated with poor overall survival (OS) in obese CRC patients, but not in their non-obese counterparts, suggesting its potential as a prognostic marker of obese CRC patients. MPS-1 expression was positively associated with circulating leptin levels in CRC patients, especially in obese cases. Functional experiments demonstrated that MPS-1 silencing inhibited tumor proliferation and colony formation, and induced apoptosis of CRC cells in vitro. Converse results were obtained from the experiments with MPS-1 over-expression. Mechanistically, MPS-1 executed its action through induction of c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moreover, the promotion effect of MPS-1 on CRC progression was modulated by leptin. In vivo studies demonstrated that MPS-1 silencing suppressed tumor growth of CRC via inhibiting JNK/c-Jun signaling. Collectively, this study indicates that MPS-1 promotes leptin-induced CRC via activating JNK/c-Jun pathway. MPS-1 might represent a potent candidate for the treatment and prognostic prediction of obesity-associated CRC.

Topics: Caco-2 Cells; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Leptin; Male; MAP Kinase Kinase 4; Metalloproteins; Nuclear Proteins; Proto-Oncogene Proteins c-jun; Ribosomal Proteins; RNA-Binding Proteins; Signal Transduction

Colorectal cancer affects the large intestine, leading to loss of white adipose tissue (WAT) and alterations in adipokine secretion. Lower incidence of colorectal cancer is associated with increased fibre intake. Fructooligosaccharides (FOS) are fibres that increase production of butyrate by the intestinal microbiota. Tributyrin, a prodrug of butyric acid, exerts beneficial anti-inflammatory effects on colorectal cancer. Our aim was to characterise the effects of diets rich in FOS and tributyrin within the context of a colon carcinogenesis model, and characterise possible support of tumorigenesis by WAT. C57/BL6 male mice were divided into four groups: a control group (CT) fed with chow diet and three colon carcinogenesis-induced groups fed either with chow diet (CA), tributyrin-supplemented diet (BUT), or with FOS-supplemented diet. Colon carcinogenesis decreased adipose mass in subcutaneous, epididymal, and retroperitoneal tissues, while also reducing serum glucose and leptin concentrations. However, it did not alter the concentrations of adiponectin, interleukin (IL)-6, IL-10, and tumour necrosis factor alpha (TNF)-α in WAT. Additionally, the supplements did not revert the colon cancer affected parameters. The BUT group exhibited even higher glucose tolerance and levels of IL-6, VEGF, and TNF-α in WAT. To conclude our study, FOS and butyrate supplements were not beneficial. In addition, butyrate worsened adipose tissue inflammation.

Topics: Adiponectin; Adipose Tissue, White; Animals; Blood Glucose; Butyrates; Colon; Colorectal Neoplasms; Dietary Supplements; Inflammation; Interleukin-6; Leptin; Male; Mice, Inbred C57BL; Oligosaccharides; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

The obesity epidemic is associated with increases in the incidence of several types of cancer, including colorectal cancer, and is associated with poor outcomes for patients. Adipose tissue is considered biologically active and represents a plausible link between cancer and obesity due to the many factors that it secretes. In the present study, human adipose tissue was cultured in vitro and predifferentiated adipocyte secretome [preadipocyte (PAS)] and differentiated adipocyte secretome (DAS) were collected. Quantification of interleukin-6 (IL-6), leptin and hepcidin in the DAS medium was compared to the PAS medium. Fold change levels of hepcidin, leptin and IL-6 in DAS (2.88±0.28, 12.34±0.95 and 31.29±1.89 fold increases) were significantly higher compared to these in PAS (p=0.05). The SW480 colorectal cancer cells were co-cultured with DAS in the presence or absence of leptin, IL-6 or hepcidin inhibitors and cellular viability and proliferation assays were performed. The culture of SW480 with DAS increased the cell proliferation and viability by 30 and 15% (p=0.02 and p=0.03) respectively, which was reversed in the presence of inhibitors. Challenging the SW480 cells with IL-6 or hepcidin significantly elevated colonocyte‑secreted leptin (p=0.05). Challenging the SW480 cells with leptin or hepcidin resulted in elevated levels of colonocyte-secreted IL-6 (p=0.05). Similarly, challenging cells with either IL-6 or leptin markedly elevated the level of secreted hepcidin (p=0.05) and this was associated with an induction in colonocyte iron levels in both cases. Collectively, these data revealed that adipocyte-secreted factors can ultimately modulate colonocyte iron levels and phenotype.

Topics: Adipocytes; Aged; Body Mass Index; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Colorectal Neoplasms; Female; Hepcidins; Humans; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Up-Regulation; Wnt Signaling Pathway

Leptin phenotype has been suggested to be a possible biomarker for the diagnosis and prognosis of different neoplasms. Nonetheless, there are conflicts among the outcomes found in several tumors, and little is proven concerning the correlation between the phenotype of leptin and its clinical significance in colorectal carcinomas. This study will describe the phenotype of leptin in colorectal adenocarcinomas, and investigate its correlation with clinicopathological factors.Two hundred and twenty eight tissue samples include 155 colorectal carcinomas, 40 adenomas, and 33 noncancerous cases were utilized in constructing tissue microarrays which have been used in the revealing of leptin expression using leptin monoclonal antibody and immunohistochemistry staining protocol.Immunoexpression of leptin was recognized in 145 (93.5%) of colorectal tumors and 56 (76.7%) cases of control group. Histotype was considerably associated with leptin phenotype (P = .000), there is up regulation in leptin expression in colorectal carcinoma cases. Significantly higher proportion of negative leptin immunostaining cases were observed in tumors which have size more than 5 cm (P = .045). Whereas, significant different survival patterns were observed in positive cases regarding tumor size, lymphovascular invasion, distant metastasis, local recurrence and relapse of disease (P-values .046, .011, .000, .013, and .001, respectively). On the other hand, positive leptin staining colorectal tumors with size <5 cm, and with no distant metastases, local recurrence, or disease relapse had significantly better survival estimates. However, leptin immunostaining did not show noteworthy associations with age, gender, differentiation, tumor location, stage, margins involvement, lymphovascular invasion, and lymph node metastasis.The current study shows up regulation in leptin expression in colorectal adenocarcinoma compared with noncancerous control cases. Thus, immunohistochemical staining of leptin in colorectal cancer could be a helpful tool in the prediction of prognosis and survival pattern of colorectal cancer with certain clinicopathological factors (tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease).

Topics: Adenocarcinoma; Adenoma; Adult; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phenotype; Prognosis; Saudi Arabia; Survival Analysis; Tumor Burden

High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk.. We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance.. Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men.. Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Body Mass Index; Colorectal Neoplasms; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Sex Factors

Adipokines are molecules produced and secreted by adipose tissue and are linked to multiple malignancies. Adipokines can suppress or promote particular cell behaviors in different types of cancer. The aim of this study was to investigate the impact of chemotherapy on select adipokines in patients with colorectal cancer (CRC). Blood samples were collected from 42 patients with pathologically documented advanced CRC, who required palliative chemotherapy. Leptin, adiponectin, resistin and visfatin levels were measured by ELISA before and 3 months after the administration of chemotherapy. Among the 42 patients evaluated, 18 achieved a partial response (PR), 16 achieved stable disease (SD) and 8 patients experienced disease progression (PD). We found that 5-fluorouracil-based chemotherapy regimens significantly increased plasma levels of leptin and adiponectin and decreased plasma levels of resistin and visfatin in PR and SD patients, whereas the plasma levels of these molecules were not affected in PD patients. Furthermore, the mean plasma levels of leptin were significantly lower, and the mean plasma levels of resistin and visfatin were significantly greater in patients with PD compared with PR and SD both before and after chemotherapy treatment. We conclude that palliative chemotherapy in CRC patients, in addition to providing clinical benefits, positively affects cytokine production and secretion in PR and SD patients. Specifically, we found that palliative chemotherapy increased plasma levels of the anti-inflammatory adipokine adiponectin and decreased the plasma levels of visfatin and resistin, molecules known to promote angiogenesis and cancer cell proliferation in PR and SD patients. Moreover, the baseline values of leptin, visfatin and resistin might serve as prognostic indicators of a poor response to chemotherapy.

Topics: Adipokines; Adiponectin; Adipose Tissue; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Prognosis; Resistin

VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Body Mass Index; Cell Line, Tumor; Colorectal Neoplasms; Humans; Kaplan-Meier Estimate; Leptin; Melanoma, Experimental; Mice; Mice, Obese; Proportional Hazards Models; Quinazolines; Retrospective Studies; Transcriptome; Treatment Outcome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

There is an established link between obesity related metabolic derangement and colorectal cancer development. Recently, we developed a metabolic-colorectal cancer risk score. In this follow-up study, we studied its association with colorectal neoplasm by measuring two major metabolic syndrome biomarkers, leptin and adiponectin.. To evaluate the serum levels of leptin and adiponectin in patients with colorectal polyps and colorectal cancer and to determine any correlation with metabolic risk score.. In total, 130 individuals were studied: 30 controls without colonic pathology, 18 with colonic adenoma (CAP), and 82 with colorectal adenocarcinoma (CRC, 17 cases of T1-2 and 65 cases of T3-4). The metabolic risk scores in CAP and T1-2 CRC were higher than those in the controls and T3-4 CRC cases. There were no statistically significant differences in leptin levels among CAPs, CRCs, and controls. Both leptin and adiponectin levels reflected differences in body mass index and metabolic risk scores. Cases in the CAP group and early T-stage CRC groups had lower adiponectin levels (14.03 and 13.01 mg/ml, respectively) than the no polyps group (19.5mg/ml, p = 0.03). The average serum adiponectin level in the invasive cancer group (18.5 ng/ml) was comparable with that of the control group.. The level of serum adiponectin was positively correlated with the metabolic risk score. Decreased serum adiponectin was significantly associated with the development of colorectal adenoma and early stage colorectal carcinoma.

Topics: Adenocarcinoma; Adenoma; Adiponectin; Biomarkers, Tumor; Case-Control Studies; Cell Transformation, Neoplastic; Colonic Polyps; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Risk Factors

There is no information on the effects of leptin receptors expression on mucin-histochemical alterations in human colorectal adenocarcinoma.. Testing the correlation of leptin receptors expression with histochemical dysregulation of mucins in colorectal adenocarcinoma.. The study included 75 patients with colorectal adenocarcinoma who underwent surgical resection. Following a routine histopathological tissue analysis, 3-4 μm thick cuts were made onto resected tumors, which underwent a routine Hematoxylin-Eosin, histochemical Alcian Blue-Periodic Acid Schiff, pH 2.5, and High Iron Diamine-Alcian Blue, pH 2.5, methods for mucin differentiation and immunohistochemical Avidin-Biotin peroxidase complex method with anti-Ki67 and anti-leptin receptor antibodies. Following the quantification of results for the statistical analysis, the statistical software package SPSS for Windows (13.0) was used, and the tests for analyzing the significance of differences and correlation analysis - Spearman's rank correlation coefficient, were conducted.. Increased expression of leptin receptors is with highly significant correlation coefficient associated with hypersecretion of sialomucins. Significant positive correlation coefficient exists between the leptin receptors expression against neutral-fucomucins secretion. With weak and negative, but a significant correlation coefficient, leptin receptors expression is associated to the sulfomucins generation.. Increased expression of leptin receptors in colorectal adenocarcinoma is associated with mucin-histochemical abnormalities that are manifested by sialomucins hypersecretion and reduction, ultimately resulting in the absence of sulfomucins secretion.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cell Differentiation; Cell Proliferation; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Ki-67 Antigen; Leptin; Male; Middle Aged; Mucins; Receptors, Leptin; Sialomucins

To investigate the roles of serum insulin, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding proteins (IGFBPs) in the initiation and progression of colorectal cancer.. We determined serum insulin, IGF-1 and IGFBPs levels in 615 colorectal cancer patients and 650 control healthy donors by enzyme-linked immunosorbent assay (ELISA). In the meantime, their body mass index (BMI) and waist-to-hip ratio (WHR) were measured.. Serum levels of insulin and IGF-1 as well as IGF-1/IGFBP-3 ratio in pre-operation patients were significantly elevated, but the level of IGFBP-3 was significantly decreased compared with normal controls and post-operation patients (P < 0.05 and P < 0.001, respectively). There is no significant difference (P > 0.05) in the levels of insulin, IGF-1, IGFBP-1, IGFBP-3 and IGF-1/IGFBP-3 between the patients with and without hepatic as well as distal abdominal metastases. WHR and BMI of colon cancer patients were positively and significantly correlated with the levels of insulin and IGF-1/IGFBP-3. In contrast, WHR and BMI were negatively correlated with IGFBP-3 level.. The elevation of insulin, IGF-1 as well as IGF-1/IGFBP-3 ratio and the reduction of IGFBP-3 may be related to the initiation of colorectal cancer, but they are not related to the progression and outcome of the disease.

Topics: Adolescent; Adult; Aged; Body Mass Index; Colorectal Neoplasms; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Risk Factors; Waist-Hip Ratio; Young Adult

Leptin, which is encoded by the obese gene, is a multifunctional neuroendocrine peptide that regulates appetite, bone formation, reproductive function and angiogenesis. The aims of the present study were to investigate the expression of leptin in 80 patients with colorectal cancer (CRC) and to determine the effects of leptin on the malignant properties of CRC cells. We evaluated the expression of leptin in tissues of 80 patients with CRC. Suspension cultures were used to isolate CRC stem cells following pretreatment with leptin. We analyzed the effects of leptin on the adhesion and invasive capacities of CRC cell lines. The effects of leptin on JAK and ERK activation were examined using western blotting. Leptin expression was associated with CRC progression and increased the number and size of spheroid formation by CRC cell lines. Leptin enhanced cell invasion and adhesion and activated JAK and ERK signaling in the CRC cell lines. The present study demonstrated that leptin influences the growth and survival of CRC stem cells and regulates adhesion and invasion of colorectal carcinoma through activation of the JAK and ERK signaling pathways.

Topics: Apoptosis; Biomarkers, Tumor; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinases; Leptin; Male; MAP Kinase Signaling System; Neoplasm Invasiveness; Neoplasm Staging

The objective of the present study was to investigate the effect of leptin on the progression of colorectal carcinoma to metastatic disease by analyzing the serum leptin concentration and Ob-R gene expression in colon cancer tissues. Tissue samples were obtained from 31 patients who underwent surgical resection for colon (18 cases) and metastatic colon (13 cases) cancer. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA) and Ob-R mRNA expression by real-time polymerase chain reaction (RT-PCR) for both groups. ELISA data were analyzed by the Student t-test and RT-PCR data were analyzed by the Mann-Whitney U-test. RT-PCR results demonstrated that mRNA expression of Ob-R in human metastatic colorectal cancer was higher than in local colorectal cancer tissues. On the other hand, mean serum leptin concentration was significantly higher in local colorectal cancer patients compared to patients with metastatic colorectal cancer. The results of the present study suggest a role for leptin in the progression of colon cancer to metastatic disease without weight loss. In other words, significantly increased Ob-R mRNA expression and decreased serum leptin concentration in patients with metastatic colon cancer indicate that sensitization to leptin activity may be a major indicator of metastasis to the colon tissue and the determination of leptin concentration and leptin gene expression may be used to aid the diagnosis.

Topics: Aged; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Real-Time Polymerase Chain Reaction; Receptors, Leptin; RNA, Messenger

Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.. A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13-1.76) and 1.74 (95%CI 1.08-2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82 × 10(-10)).. Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.

Topics: Case-Control Studies; Colorectal Neoplasms; Female; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Leptin; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Receptors, Leptin; Smoking

Adipokines are adipocyte-secreted hormones that may mediate the etiologic link between obesity and colorectal cancer; however, the evidence from large prospective studies is limited. We prospectively evaluated the association of plasma adiponectin and soluble leptin receptor (sOB-R) with colorectal cancer risk within the Nurses' Health Study (1990-2008) and the Health Professionals Follow-up Study (1994-2008) among 616 incident colorectal cancer cases and 1,205 controls selected using risk-set sampling and matched on age and date of blood draw. In unconditional logistic regression with adjustment for matching factors and multiple risk factors, plasma adiponectin was significantly associated with reduced risk of colorectal cancer among men, but not among women. Compared with men in the lowest quartile of adiponectin, men in the highest quartile had a relative risk (RR) for colorectal cancer of 0.55 [95% confidence interval (CI), 0.35-0.86; Ptrend = 0.02]. The corresponding RR in women was 0.96 (95% CI, 0.67-1.39; Ptrend = 0.74). Plasma sOB-R was not associated with overall colorectal cancer risk in either men or women. A significant heterogeneity was noted in the association between sOB-R and colorectal cancer by subsite in women (Pheterogeneity = 0.004); sOB-R was significantly associated with increased risk of rectal cancer but not colon cancer. These findings support a role for adiponectin in colorectal carcinogenesis in men. Further studies are warranted to confirm these associations and elucidate potential underlying mechanisms.

Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Life Style; Male; Middle Aged; Prognosis; Prospective Studies; Receptors, Leptin; Risk Factors

Metabolic syndrome (MetS) describes a clustering of factors including central obesity, hypertension and raised plasma glucose, triglycerides and high-density lipoprotein (HDL) cholesterol. Central obesity is associated with a risk for colorectal cancer, but the impact of MetS on colorectal cancer biology and outcomes is unclear.. A prospective observational study of colorectal cancer patients was carried out in an Irish population. Patients underwent metabolic and anthropometric assessment before treatment, including measurement of serum hormones and adipokines and CT measurement of visceral fat. MetS was defined according to the International Diabetes Federation definition(3) .. One-hundred and thirty consecutive colorectal cancer patients (66 men and 64 women) were recruited. MetS was diagnosed in 38% patients compared with the population norms reported at 21%(21) . Male patients had a significantly greater visceral fat area compared with female patients. MetS was associated with node-positive disease (P = 0.026), percentage nodal involvement (P = 0.033) and extramural vascular invasion (P = 0.049) in male patients but no significant association was observed in female patients. HDL cholesterol was also significantly associated with a more advanced pathological stage (P = 0.014) and node-positive disease (P = 0.028). Leptin was associated with nodal status (P = 0.036), microvascular invasion (P = 0.054), advanced pathological stage (P = 0.046) and more advanced Dukes stage (P = 0.042).. We report a high prevalence of MetS and visceral obesity in a colorectal cancer population. MetS and plasma leptin are associated with a more aggressive tumour phenotype in male patients only.

Topics: Aged; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Carcinoma; Cholesterol, HDL; Cholesterol, LDL; Colorectal Neoplasms; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lymphatic Metastasis; Male; Metabolic Syndrome; Neoplasm Invasiveness; Prospective Studies; Radiography; Sex Factors; Triglycerides; Waist Circumference

We investigated the role of fasting hormones and pro-inflammatory cytokines in cancer patients. Hormones (ghrelin, adiponectin, and leptin) and cytokines (TNF-α, IFN-γ, and IL-6) were measured by ELISA or RIA in lung cancer and colorectal cancer patients before the administration of cancer therapy, and measurements were repeated every 2 months for 6 months. From June 2006 to August 2008, 42 patients (19 with colorectal cancer and 23 with lung cancer) were enrolled. In total, 21 patients were included in the cachexia group and the others served as a comparison group. No significant difference in the initial adiponectin, ghrelin, TNF-α, IFN-γ, or IL-6 level was observed between groups, although leptin was significantly lower in cachectic patients than in the comparison group (15.3 ± 19.5 vs 80.9 ± 99.0 pg/mL, P = 0.007). During the follow-up, the patients who showed a > 5% weight gain had higher ghrelin levels after 6 months. Patients exhibiting elevated IL-6 levels typically showed a weight loss > 5% after 6 months. A blunted adiponectin or ghrelin response to weight loss may contribute to cancer cachexia and IL-6 may be responsible for inducing and maintaining cancer cachexia.

Topics: Adiponectin; Aged; Antineoplastic Agents; Cachexia; Colorectal Neoplasms; Cytokines; Female; Follow-Up Studies; Ghrelin; Humans; Interferon-gamma; Interleukin-6; Leptin; Lung Neoplasms; Male; Middle Aged; Peptide Hormones; Prognosis; Prospective Studies; Survival Rate; Tumor Necrosis Factor-alpha; Weight Gain; Weight Loss

Epidemiological studies have indicated that obesity is associated with colorectal cancer. The obesity hormone leptin is considered as a key mediator for cancer development and progression. The present study aims to investigate regulatory effects of leptin on colorectal carcinoma. The expression of leptin and its receptor Ob-R was examined by immunohistochemistry in 108 Chinese patients with colorectal carcinoma. The results showed that leptin/Ob-R expression was significantly associated with T stage, TNM stage, lymph node metastasis, distant metastasis, differentiation and expression of p-mTOR, p-70S6 kinase, and p-Akt. Furthermore, the effects of leptin on proliferation and apoptosis of HCT-116 colon carcinoma cells were determined. The results showed that leptin could stimulate the proliferation and inhibit the apoptosis of HCT-116 colon cells through the PI3K/Akt/mTOR pathway. Ly294002 (a PI3K inhibitor) and rapamycin (an mTOR inhibitor) could prevent the regulatory effects of leptin on the proliferation and apoptosis of HCT-116 cells via abrogating leptin-mediated PI3K/Akt/mTOR pathway. All these results indicated that leptin could regulate proliferation and apoptosis of colorectal carcinoma through the PI3K/Akt/ mTOR signalling pathway.

Topics: Apoptosis; Asian People; Cell Proliferation; Chromones; Colorectal Neoplasms; Humans; Immunohistochemistry; Leptin; Morpholines; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To investigate the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARG) in relation to body mass index (BMI).. We evaluated leptin and PPARG expression in 30 adenomas over 1 cm in size by immunohistochemical staining. In addition, clinicopathologic features including BMI were assessed.. PPARG and leptin expression showed a strong positive correlation (P = 0.035). The average BMI of the leptin-positive group was higher than that of the leptin-negative group (25.4 ± 3.4 kg/m(2)vs 22.6 ± 2.4 kg/m(2), P = 0.018), and leptin expression was significantly correlated with high BMI (P = 0.024). Leptin expression was more frequently observed in intermediate/high grade dysplasia than in low grade dysplasia (P = 0.030). However, PPARG expression was not correlated with BMI and grade of dysplasia.. BMI has influenced on the leptin expression of colorectal adenoma. The exact mechanism underlies the strong correlation between leptin and PPARG expression needs further study.

Topics: Adenoma; Adult; Body Mass Index; Cell Line, Tumor; Colorectal Neoplasms; Female; Humans; Leptin; Male; Microarray Analysis; Middle Aged; Obesity; PPAR gamma

Obesity is associated with an increased risk of colon cancer. High-fat diets that lead to obesity may be a contributing factor, but the mechanisms are unknown.. This study examines susceptibility to azoxymethane (AOM)-induced precancerous lesions in mice in response to consumption of either a low or a high-fat diet and associated molecular changes in the liver and colon.. Gene markers of xenobiotic metabolism, leptin-regulated inflammatory cytokines and proliferation were assessed in liver and colon in response to high-fat feeding to determine links with increased sensitivity to AOM.. High-fat feeding increased development of AOM-induced precancerous lesions and was associated with increased CYP2E1 gene expression in the liver, but not the colon. Leptin receptors and the colon stem cell marker (Lgr5) were down-regulated in the proximal colon, with a corresponding up-regulation of the inflammatory cytokine (IL6) in response to high-fat feeding. Notably in the distal colon, where aberrant crypt foci develop in response to AOM, the proliferative stem cell marker, Lgr5, was significantly up-regulated with high-fat feeding.. The current study provides evidence that high-fat diets can alter regulation of molecular markers of xenobiotic metabolism that may expose the colon to carcinogens, in parallel with activation of β-catenin-regulated targets regulating colon epithelial cells. High-fat diets associated with obesity may alter multiple molecular factors that act synergistically to increase the risk of colon cancer associated with obesity.

Topics: Aberrant Crypt Foci; Animals; Body Composition; Colon; Colorectal Neoplasms; Cytochrome P-450 CYP2E1; Cytokines; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Gene Expression Regulation; Incidence; Leptin; Liver; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Receptors, Leptin

Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P(trend) = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P(trend) = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P(trend) = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P(trend) = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis.

Topics: Adult; Aged; Cohort Studies; Colorectal Neoplasms; Europe; Female; Humans; Leptin; Male; Middle Aged; Nutritional Status; Prospective Studies; Receptors, Leptin

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator- activated receptor γ(PPARγ) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ay obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.

Topics: Aberrant Crypt Foci; Adipokines; Animals; Azoxymethane; Biomarkers; Carcinogens; Colorectal Neoplasms; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Hypoglycemic Agents; Immunoenzyme Techniques; Insulin; Intra-Abdominal Fat; Leptin; Lipids; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; PPAR gamma; Thiazolidinediones

Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters.. Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD).. Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients.. The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cell Transformation, Neoplastic; Chemokine CCL2; Colorectal Neoplasms; Female; Humans; Inflammation; Interleukin-1alpha; Leptin; Male; Middle Aged; Obesity, Morbid; Plasminogen Activator Inhibitor 1; Resistin; Tumor Necrosis Factor-alpha; Young Adult

To investigate the expression and biological significance of Leptin, Leptin receptor, Vascular Endothelial Growth Factor (VEGF), and CD34 protein in colorectal carcinoma tissues. The expression of Leptin, Leptin receptor, VEGF, and CD34 was detected in 68 cases of colorectal carcinoma tissues, paired para-carcinoma tissues and normal colorectal tissues by Immunohistochemical SP Method. The results and related clinicopathological data were analyzed. The positive rate of Leptin, Leptin receptor, and VEGF was significantly higher in colorectal carcinoma tissues than that in paired para-carcinoma tissues and normal colorectal tissues. The expression of Leptin, Leptin receptor, and VEGF was correlated with grade of tumor differentiation, depth of bowel wall invasion, lymph node metastasis, Dukes stage, distant metastasis, and lympho/vascular tumor embolization. Microvessel density (MVD) value in colorectal carcinoma was significantly higher than that in para-carcinoma tissues and normal colorectal tissues, and the density in para-carcinoma tissues was higher than that in normal colorectal tissues. The expression of Leptin, Leptin receptor, VEGF, and MVD value in colorectal carcinoma was positively correlated. In conclusion, microvessel density value is an important index of the growth, invasion, and metastasis of colorectal carcinoma. The binding of Leptin and Leptin receptor promotes the proliferation of colorectal carcinoma cells. The synergy between Leptin and VEGF accelerates the angiogenesis in colorectal carcinoma and accelerates the invasion and metastasis of the tumor cells.

Topics: Adult; Aged; Antigens, CD34; Carcinoma; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Receptors, Leptin; Vascular Endothelial Growth Factor A

The possible role of leptin in colorectal tumors has been investigated in previous studies; however, to date, the conclusions remain under debate. Therefore, we investigated the serum leptin levels in colorectal adenoma patients. In addition, expression of the leptin receptor, and the leptin receptor-mediated signaling pathways were investigated in biopsy specimens collected from human patients with colorectal adenoma. No significant difference in the mean serum leptin level was observed between the colorectal adenoma patients and the control subjects; however, increased expression and activation of the leptin receptor, as indicated by findings such as the phosphorylation of Tyr 1141, was observed in the colorectal adenoma tissues. In addition, activation of the JAK/STAT signaling pathway mediated by the leptin receptor and increased transcriptional regulation of downstream target molecules were observed in colorectal adenomas compared with the non-adenoma tissues. These results indicate STAT3-mediated leptin receptor signaling pathways may be activated in human colorectal adenomas.

Topics: Adenoma; Blotting, Western; Colorectal Neoplasms; Enzyme Activation; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor

Obesity increases the risk of colorectal cancer (CRC). Serum leptin levels are markedly elevated in obese individuals, but the involvement of leptin in CRC growth remains unclear. We explored the hypothesis that leptin signalling regulates the growth of CRC, by examining the effects of leptin deficiency on murine colon tumour growth.. We used genetic (leptin-deficient and leptin receptor-deficient) models of obesity and investigated carcinogen-induced colon polyp formation and cell proliferation in the colonic epithelium. Colonic tissues and cell lines were analysed by histopathology and molecular-biology methods.. A significant increase in the proliferative activity of normal colonic epithelial cells was observed in the obesity model; on the other hand, significant decrease of tumour cell proliferation was observed in leptin-deficient tumours, and tumour growth was dramatically inhibited in leptin-deficient and leptin-receptor-deficient mice despite the animals exhibiting severe obesity. Notably, a marked increase of the leptin receptor (ObR) expression levels was observed in colon tumours as compared to the normal epithelium. Nuclear β-catenin staining was pronounced in all tumours, irrespective of leptin deficiency, whereas altered cellular localisation of β-catenin was not observed in the normal colonic epithelial cells. In vitro, β-catenin knockdown decreased ObR expression, and stimulation of recombinant Wnt increased ObR expression. In addition, the proliferative and survival effects of leptin were found to be mediated by the ObR/signal transducer and activator of transcription 3 (STAT3) signalling in colon tumours.. Our findings indicate that leptin is important for CRC growth in obesity, and acts as a growth factor for CRC at stages subsequent to tumour initiation in colorectal carcinogenesis. Thus, inhibition of leptin signalling may be an effective strategy for therapy and prevention of colonic adenoma and cancer, which show activation of Wnt signalling.

Topics: Animals; Apoptosis; Colorectal Neoplasms; Disease Progression; Gene Expression Regulation, Neoplastic; Immunoblotting; Immunohistochemistry; Leptin; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Obesity; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Tumor Cells, Cultured

Obesity increases colorectal cancer (CRC) risk and progression. However, the impact of obesity on CRC in women is dependent on ovarian hormone status. The purpose of this study was to determine the interactive roles of obesity and ovarian hormones on serum markers of inflammation, cell signaling, and transplanted colon tumor growth. Female C57BL/6 mice (6 wk) were either ovariectomized (OVX) or ovaries left intact (nonovariectomized, NOVX) and randomized to receive a (1) control, (2) 30% calorie-restricted (CR), or (3) diet-induced obese (DIO) diet regimen for 20 wk to induce differing levels of adiposity. Serum was collected and inflammatory and metabolic markers were measured using an antibody array (62 proteins) and ELISAs. Mice were subcutaneously injected with syngeneic MC38 colon cancer cells after 20 wk and sacrificed 4 wk later. CR mice had the smallest tumors irrespective of hormone status, whereas the largest tumors were observed in DIO-OVX mice. Glucose tolerance was impaired in OVX mice, being most severe in the DIO-OVX group. Cytokine arrays suggested that in CR animals, inhibition of tumor growth paralleled insulin sensitivity and associated changes in leptin, adiponectin, and IGF-BPs. Conversely, in DIO-OVX animals, tumor growth was associated with insulin and leptin resistance as well as higher levels of pro-inflammatory proteins. In vitro, leptin and adiponectin had no effect, whereas insulin induced MC38 cell proliferation and MAPK activation. Co-treatment with estrogen blocked the stimulatory effects of insulin. Thus, our in vitro and in vivo data indicate female reproductive hormones have a modulating effect on obesity-induced insulin resistance and inflammation, which may directly or indirectly influence CRC progression.

Topics: Animals; Blotting, Western; Caloric Restriction; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cytokines; Dietary Fats; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Estrogens; Extracellular Signal-Regulated MAP Kinases; Female; Hypoglycemic Agents; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Neoplasm Transplantation; Obesity; Ovariectomy; Phosphorylation; Random Allocation

Although a number of recent studies have reported the involvement of leptin in colorectal carcinogenesis, findings are contradictory and difficult to interpret. Our group has previously reported that leptin signaling might have an important role in the development of colorectal adenomas. In this study, we investigated leptin signaling in colorectal carcino-genesis focusing in particular on the differences in leptin signaling between colorectal adenoma and cancer. Whereas no significant differences in the serum leptin levels were observed among normal control subjects and adenoma/cancer patients, increased expression and activation of the long form leptin receptor (ObRL) was observed in colorectal adenoma and cancer tissues compared with the normal colorectal tissues. However, no significant differences were observed between the colorectal adenoma and cancer tissues. Significant increases in the phosphorylation levels of important molecules of the JAK/STAT signaling pathway, located downstream of leptin signaling, and transcriptional regulation of STAT3-downstream target molecules were observed in colorectal adenoma tissue compared with the findings in normal colorectal tissues. Furthermore, these changes were significantly more pronounced in colorectal cancer compared to colorectal adenoma tissues. This is the first analysis of leptin and JAK/STAT signaling in a human colorectal adenoma-carcinoma sequence. These results suggest that the STAT3-mediated leptin signaling through the activation of ObRL may be involved in colorectal carcinogenesis, both in adenoma formation and in the progression to cancer. STAT3 signaling in colorectal cancer may be mediated not only by leptin but by other factors.

Topics: Adenoma; Case-Control Studies; Colorectal Neoplasms; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinases; Leptin; Male; Middle Aged; Phosphorylation; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor

The leptin receptor is involved in modulating leptin activity, acting as a carrier protein. A link between leptin or leptin receptor and cancer development has been proposed and here, the hypothesis that leptin and its receptor might be implicated in colorectal cancer (CRC) progression and invasion was investigated.. A total of 71 consecutive patients with CRC were enrolled in the study. Serum leptin and leptin receptor levels were evaluated by commercial ELISA kits.. The multinomial logistic regression model showed a positive association of leptin and leptin receptor with advanced tumor stages, which was significant for the leptin receptor in stage IV of disease.. High circulating levels of leptin receptor occur in patients with advanced stage of colon cancer, suggesting a role for leptin in cancer progression and aggressiveness.

Topics: Aged; Colorectal Neoplasms; Demography; Female; Humans; Leptin; Logistic Models; Male; Neoplasm Staging; Receptors, Leptin; Solubility

Obesity is a risk factor for colorectal cancer and adenomatous polyps. The increased prevalence of neoplasia coupled with the observation that obesity may be associated with a suboptimal bowel preparation may diminish the adequate detection of adenomas for obese who undergo colonoscopy. The colonic complications of obesity are reviewed in this article.

Topics: Adenoma; Animals; Body Mass Index; Colonic Diseases; Colonoscopy; Colorectal Neoplasms; Comorbidity; Diverticulitis, Colonic; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Obesity

Adipocytokines are adipocyte-secreted hormones associated with some malignancies such as colorectal, breast, and prostate cancer. We hypothesized that changes in the levels of adipocytokines may indicate the carcinogenesis and progression of colorectal cancer and adenoma, and investigated the association of the blood levels of several adipocytokines through a case-control study. Blood levels of adiponectin, leptin, resistin, visfatin, and C-peptide at diagnosis were measured in 115 colorectal cancer patients and 115 age-, sex-, and body mass index-matched controls. The same analysis was performed in 72 colorectal adenoma patients and 72 controls. Logistic regression models were used for estimating odds ratios and 95% confidence intervals, and one-way anova was performed to determine the prevalence of each variable between two or more groups. Resistin and visfatin levels in cancer patients were significantly higher than those of controls on multivariate analysis (P = 0.03 and P < 0.01, respectively). Stage progression significantly correlated with resistin and visfatin levels (P < 0.01 for both). The adiponectin level in adenoma patients was significantly lower than that of controls on multivariate analysis (P = 0.04). Its level was inversely correlated with the number of adenoma (P = 0.02), but not correlated with the size of adenoma. Resistin and visfatin may be good biomarkers of colorectal malignant potential and stage progression. Adiponectin level may be a good biomarker of colorectal adenoma.

Topics: Adenoma; Adipokines; Adiponectin; Adult; Aged; Biomarkers, Tumor; Body Mass Index; C-Peptide; Colorectal Neoplasms; Cytokines; Female; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin

Dietary red and processed meats may increase risk of colorectal cancer (CRC), whereas fiber may be protective. Recently, we demonstrated that dietary beef causes greater colonic DNA strand breakage than equivalent levels of chicken in rats and that resistant starch (RS) as 20% high amylose maize starch (HAMS) attenuated the damage. From that study, we now report measures of circulating factors that may influence CRC initiation or progression including malondialdehyde (MDA), leptin, insulin-like growth factor-I (IGF-I), insulin, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), interleukins (IL), and short chain fatty acids. MDA levels were increased by beef diets relative to the chicken diets. Leptin concentrations, which were lower for chicken than beef at the 35% level in the absence of HAMS, were lowered by HAMS. Higher dietary chicken (but not beef) increased IGF-I irrespective of HAMS feeding. Higher levels of chicken resulted in greater insulin concentrations than for beef in rats fed HAMS. Without dietary HAMS, TIMP-2 concentration increased in response to both meats but was highest for chicken. MMP-2 and TIMP-2 concentrations were higher for HAMS diets. IL-1beta and IL-12 concentrations were lowered by HAMS feeding. Colonic DNA strand breakage was positively associated with circulating leptin and MDA concentrations as well as tissue MDA concentrations and negatively associated with plasma TIMP-2 concentration. MMP-2 and TIMP-2 positively correlated with hepatic portal butyrate levels but leptin concentrations correlated negatively. These results suggest diets high in meat or RS could influence cancer initiation or progression by changes in circulating levels of hormones and other factors.

Topics: Amylose; Animals; Cattle; Chickens; Colon; Colorectal Neoplasms; DNA Breaks; Fatty Acids, Volatile; Insulin; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Interleukins; Intestinal Mucosa; Leptin; Liver; Male; Malondialdehyde; Matrix Metalloproteinase 2; Meat; Random Allocation; Rats; Rats, Sprague-Dawley; Starch; Tissue Inhibitor of Metalloproteinase-2

Serum adiponectin, leptin, C-peptide, and homocysteine are indicators for obesity, hyperinsulinemia, and chronic inflammation, which have all been associated with colorectal cancer.. To determine whether serum adiponectin, leptin, C-peptide, and homocysteine are associated with fat, fiber, fruit and vegetable, flavonol, or dry bean intake and colorectal adenoma recurrence.. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (95% CI) for adenoma recurrence in 627 participants from the control arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence.. Serum concentrations of C-peptide and homocysteine were inversely related to fiber, fruit and vegetable, and flavonol intake and positively related to percentage of calories from fat (all P(trend) < or = 0.01). High homocysteine concentrations were associated with any (4th versus 1st quartile: OR, 2.26; 95% CI, 1.30-3.94) and more than one adenoma recurrence (OR, 2.11; 95% CI, 1.01-4.40). Individuals in the highest, versus lowest, tertile of serum leptin concentration had a decreased risk of advanced adenoma recurrence (OR, 0.22; 95% CI, 0.06-0.79).. Our results suggest that serum homocysteine may serve as an indicator of dietary exposure, including a low-fat and high-fiber, high-fruit and vegetable, and high-flavonol diet, as well as colorectal adenoma recurrence.. Discovering biomarkers that are both modifiable and can predict cancer risk is critical. We identified serum homocysteine as a novel indicator that is modified by diet and predicts risk of adenoma recurrence.

Topics: Adenoma; Adiponectin; Adult; Aged; Aged, 80 and over; C-Peptide; Colorectal Neoplasms; Diet; Female; Follow-Up Studies; Homocysteine; Humans; Leptin; Male; Middle Aged; Neoplasm Recurrence, Local; Recurrence; Risk Factors

Obesity has been associated with an increased risk of colorectal neoplasia, but the mechanisms of this potential association have not been elucidated. We hypothesized that the adipokines adiponectin, leptin, and tumor necrosis factor-alpha (TNF-alpha) may mediate an association between obesity and colorectal cancer. We measured plasma concentrations of total and high-molecular-weight (HMW) adiponectin, leptin, and TNF-alpha in healthy volunteer examinees who underwent total colonoscopy between February 2004 and February 2005, and conducted a case-control study consisting of 778 cases and 735 controls. An inverse association of total and HMW adiponectin was observed with colorectal adenoma (P trend < 0.001 and 0.03, respectively). Further, total adiponectin interacted with leptin, but not TNF-alpha, in relation to colorectal adenoma (P interaction = 0.007). An inverse association of total adiponectin with colorectal adenoma was apparent in the highest two tertiles of leptin, particularly the middle (P trend < 0.001), whereas a positive association of leptin was obvious in the lowest tertile of total adiponectin (P trend = 0.01) after adjusting for potential confounders and body mass index, which is a major determinant of insulin resistance. Adiponectin may exert an anticarcinogenic effect on the large intestine by interfering with leptin, whereas leptin could conversely exert a carcinogenic effect under conditions of a lower abundance of adiponectin. Our findings provide the first epidemiologic evidence for interactive effects of adiponectin and leptin in the early stage of colorectal tumorigenesis, distinct from their involvement in insulin resistance.

Topics: Adenoma; Adiponectin; Adult; Aged; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Risk Factors; Tumor Necrosis Factor-alpha

The incidence of colon cancer has increased in developed countries, possibly due to sedentary lifestyle and high caloric diet. Experimental and epidemiological evidence suggests a link between colon cancer development and adipose tissue-derived circulating hormones. Leptin, a pluripotent cytokine secreted by adipocytes, is a key regulator of appetite and energy balance acting in the brain. On the other hand, leptin also controls many physiological and pathological processes in peripheral organs. Recent studies in colon cancer cell lines and human tumors suggested that leptin and its receptor (ObR) are implicated in colon carcinogenesis, and may serve as new biomarkers and pharmacological targets. Here, we explored, for the first time, whether leptin can affect the biology of colorectal tumor stem cells (CTSCs). We found that our previously established and characterized CTSC clones express ObR and respond to leptin with cell proliferation, activation of the extracellular signal-related kinase (ERK)1/2 and AKT signaling pathways, enhanced growth in soft agar, and improved sphere formation associated with E-cadherin overexpression. Moreover, leptin counteracted cytotoxic effects of 5-fluorouracil, a common colon cancer therapeutic agent. These results suggest that obesity and increased leptin levels might promote colorectal cancer by increasing growth and survival of CTSCs.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Colony-Forming Units Assay; Colorectal Neoplasms; Fluorouracil; Humans; Leptin; Neoplastic Stem Cells; Obesity; Receptors, Leptin; Signal Transduction

Colorectal adenoma and cancer are known to be associated with obesity. Leptin, an adipocyte-derived hormone that plays a crucial role in obesity has been suggested as a growth factor in colon cancer. However, the association between adenoma and leptin remains controversial. We evaluated the leptin expression in human colorectal adenoma and its correlation to clinicopathologic factors.. Leptin expression was assessed by immunohistochemistry in 91 samples of colorectal adenoma larger than 5 mm, which were removed by endoscopic polypectomy. All patients underwent colonoscopy for cancer screening at Seoul Paik Hospital from 2007 to 2008 and we only included the patients less than 50 years of age. Leptin expression and its relationship with clinicopathologic features were analyzed.. Eighty samples were available for the interpretation of leptin expression and showed positive in 42 (52.5%) cases and negative in 38 (47.5%) cases. As body mass index (BMI) increased based on World Health Organization (WHO) classification the positivity of leptin expression also increased (ptrend=0.02). In leptin positive group, the correlation of leptin expression with adenoma size and histological showed positive tendency without statistical significance.. Leptin expression of colorectal adenoma was associated with BMI. The question of whether leptin contributes to colorectal adenoma development is unresolved and will require additional studies.

Topics: Adenoma; Adult; Body Mass Index; Colonoscopy; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Obesity

Leptin and adiponectin are cytokines produced by adipose tissue with opposite effects on tumor growth: the former stimulate whereas the latter inhibit it. The objective was to analyze the association of LEP A19G and ADIPOQ+45 T/G and +276 G/T polymorphisms in Mexican patients with colorectal cancer (CRC). 68 unrelated patients with CRC (study group) and 102 blood donors (control group); all subjects were Mestizos from western Mexico. The polymorphisms were established by PCR-RFLP on DNA samples obtained from peripheral blood. The LEP A19G polymorphism showed significant differences between CRC patients and control group (p= 0.01 for G/A genotype and p= 0.02 for the recessive model G/G +G/A); yet, in the analysis stratified by gender, this difference remained significant only in males. The ADIPOQ polymorphisms did not shown any significant differences. Our results suggest that the A19G LEP polymorphism is associated with CRC in Mexican patients.

Topics: Adiponectin; Carcinoma; Colorectal Neoplasms; Female; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Leptin; Male; Mexico; Middle Aged; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide

Genetic variability in obesity-related genes and the resulting phenotypes are being recognized as major risk factors for colorectal cancer and/or severity of the disease.. A total of 102 patients (aged 68 +/- 10.2 years, 79 men and 23 women) and 101 age-matched (68.1 +/- 5.4 years old) individuals without colorectal cancer, 59 men and 42 women, were recruited. All the individuals were genotyped for the following subset of polymorphisms in obesity-related genes: angiotensinogen gene (M235T and -6A/G), in IL-6 gene (-174 G/C and -596 A/G), in leptin gene (-2548 A/G), and polymorphism Gln223Arg within the leptin receptor (LEPR) gene.. A significant increase in frequency of double heterozygote genotype (MTAG) of both angiotensinogen polymorphisms in males with colorectal cancer was observed when compared to control men [odds ratio (OR) = 3.77, P (corr) = 0.001]. A marginally significant difference in genotype distribution of -174 G/C IL-6 polymorphism between the patients in stage I-II compared to patients in III-IV was found (P (g) = 0.05, P (a) = 0.173). The GG genotype of -174 G/C IL-6 polymorphism in the patients in stage III-IV carries an increased risk compared to those in stage I-II (OR = 2.83, P (corr) = 0.06). Similarly, a difference in genotype distribution of Gln223Arg in LEPR gene between the patients staged I-II compared to III-IV was observed (P (g) = 0.05). The AA genotype was shown to be risky for the patients staged III-IV (OR = 3.35, P (corr) = 0.06).. The investigated single nucleotide polymorphisms within the genes encoding for obesity-related genes were observed to be associated both with clinical manifestation of colorectal cancer and with severity of the disease. Thus, we suggest that defined genetic variability in the genes might become DNA markers for colorectal cancer in the future.

Topics: Aged; Angiotensinogen; Case-Control Studies; Colorectal Neoplasms; Czech Republic; Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-6; Leptin; Male; Obesity; Phenotype; Polymorphism, Single Nucleotide; Receptors, Leptin; White People

Leptin, adiponectin, and resistin are the proteins secreted by adipocytes, which affects the metabolism. While the role of leptin in colon carcinogenesis is documented, the effect of adiponectin and resistin remains unclear. It has been indicated that while leptin may potentiate the cancer cells growth, adiponectin and resistin may act oppositely.. The aim of this study is to determine the concentration of leptin, adiponectin, and resistin in patients with adenomatous polyps and colorectal cancer.. The serum concentration investigated adipohormones had been measured with ELISA in 37 patients with colorectal adenomas, 36 with colorectal cancer (CC) and in 25 controls with no colorectal pathology. Endoscopically removed polyps and CC biopsies had been evaluated with histopathology. Mean BMI value was calculated for all patients.. Among 37 adenomas, 25 revealed high-grade dysplasia (HGD) and 12 low-grade dysplasia (LGD). All cases of CC were adenocarcinomas. No difference in the level of investigated adipohormones in serum between patients with HGD and LGD polyps was observed. The serum concentration of leptin and adiponectin in CC patients was lower than in patients with adenomas (p < 0.05; p < 0.05, respectively) as well as in controls (p < 0.01; p < 0.05, respectively). The concentration of resistin in CC was not significantly different in the adenoma group (p > 0.05) but higher than in controls (p < 0.05). There was a correlation between adiponectin and leptin serum concentration (r = 0.61).. We conclude that serum concentration of adiponectin and resistin may play an important role in colon carcinogenesis. We also assume that leptin may possibly have the prognostic value useful in clinical practice and its concentration is independent of BMI value.

Topics: Adenoma; Adiponectin; Case-Control Studies; Colonoscopy; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Resistin

Leptin, the product of the ob gene, is an adipocyte-derived neurohormone that regulates body fat storage and feeding behavior. Some studies have suggested that leptin has growth-factor-like functions in epithelial cells and its abnormal expression may be involved in cancer development and progression. We investigated leptin expression in normal and neoplastic colorectal tissues and its association with clinicopathological features and clinical outcome in colorectal adenocarcinoma patients. Leptin expression was evaluated on the tissue microarray of 44 normal colon mucosal tissues, 44 adenomatous polyps, and 437 colorectal adenocarcinomas by immunohistochemistry. Data were analyzed by chi-square test, one-way analysis of variance (ANOVA), Cox regression hazards model, and log-rank test with Kaplan-Meier curves. Frequency of leptin expression was dramatically increased from normal colonic mucosa (2/44, 4.5%) to adenomas (13/44, 29.5%) and adenocarcinomas (321/437, 73.5%) as neoplastic progression. Interestingly, leptin expression was correlated with favorable tumor features in depth of invasion (p = 0.033), lymph node metastasis (p = 0.019), American Joint Committee on Cancer (AJCC) and Dukes' stage (p = 0.021 and p = 0.005, respectively), differentiation (p = 0.010), and lymphatic invasion (p = 0.003). In univariate survival analysis, patients with leptin-positive adenocarcinoma revealed better overall and disease-free survivals (p = 0.032 and p = 0.004, respectively, log-rank test). In multivariate survival analysis with Cox proportional hazards model, leptin expression was an independent prognostic marker of disease-free survival (p = 0.009). We conclude that leptin was gradually expressed during the normal-adenoma-adenocarcinoma sequence, suggesting an association in colorectal carcinogenesis. In addition, high leptin expression was an indicator of favorable tumor features and better survival of colorectal cancer patients.

Topics: Adenocarcinoma; Adenoma; Adenomatous Polyps; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Colon; Colorectal Neoplasms; Female; Humans; Immunoenzyme Techniques; Leptin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Phenotype; Survival Rate; Tissue Array Analysis; Young Adult

Examination of adipose tissue biology may provide important insight into mechanistic links for the observed association between higher body fat and risk of several types of cancer, in particular colorectal and breast cancer. We tested two different methods of obtaining adipose tissue from healthy individuals. Ten overweight or obese (body mass index, 25-40 kg/m(2)), postmenopausal women were recruited. Two subcutaneous abdominal adipose tissue samples were obtained per individual (i.e., right and left lower abdominal regions) using two distinct methods (method A: 14-gauge needle with incision, versus method B: 16-gauge needle without incision). Gene expression was examined at the mRNA level for leptin, adiponectin, aromatase, interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in flash-frozen tissue, and at the protein level for leptin, adiponectin, IL-6, and TNF-alpha following short-term culture. Participants preferred biopsy method A and few participants reported any of the usual minor side effects. Gene expression was detectable for leptin, adiponectin, and aromatase, but was below detectable limits for IL-6 and TNF-alpha. For detectable genes, relative gene expression in adipose tissue obtained by methods A and B was similar for adiponectin (r = 0.64, P = 0.06) and leptin (r = 0.80, P = 0.01), but not for aromatase (r = 0.37,P = 0.34). Protein levels in tissue culture supernatant exhibited good intra-assay agreement [coefficient of variation (CV), 1-10%], with less agreement for intraindividual agreement (CV, 17-29%) and reproducibility, following one freeze-thaw cycle (CV, >14%). Subcutaneous adipose tissue biopsies from healthy, overweight individuals provide adequate amounts for RNA extraction, gene expression, and other assays of relevance to cancer prevention research.

Topics: Adiponectin; Aromatase; Biomarkers, Tumor; Biopsy; Breast Neoplasms; Colorectal Neoplasms; Female; Gene Expression; Humans; Interleukin-6; Leptin; Obesity; Overweight; Pilot Projects; Risk Factors; RNA, Messenger; Subcutaneous Fat; Tumor Necrosis Factor-alpha

Obesity has been related to an increased risk of colorectal cancer (CRC). Adipokines produced by the adipose tissue are directly linked to obesity and may thus contribute to the pathogenesis of CRC. We hypothesized that potentially functional polymorphisms in the adipokine genes leptin (LEP), leptin receptor (LEPR), resistin (RETN), and adiponectin (ADIPOQ) may be associated with CRC.. We studied the association of four putatively functional single nucleotide polymorphisms (SNPs) with CRC risk using a hospital-based study design with 702 cases and 752 controls from the Czech Republic. We used likelihood ratio tests to select the best model to represent the relationship between genotypes and risk of CRC. Age-adjusted odds ratios (ORs) under the best model were calculated for each SNP. Previous genotyping data on insulin (INS)-related genes were used to explore interactions between genes in obesity- and diabetes-related pathways by using two independent methods, logistic regression, and multifactor-dimensionality reduction.. A trend to associate between the RETN SNP rs1862513 (C-420G) and CRC risk was observed (per allele OR 1.18, 95% confidence interval (0.99-1.40). Statistically, significant interactions were observed between the INS SNP rs3842754 (+1127INSPstI) genotypes and both the LEPR SNP rs1137101 (Q223R) and the ADIPOQ SNP rs266729 (C-11374G) genotypes.. Our results suggest that variants in the adipokine genes may affect CRC risk in combination with variants in diabetes-related genes.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Case-Control Studies; Colorectal Neoplasms; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Leptin; Resistin

Adiponectin is produced exclusively by adipose tissues. It is associated with visceral adiposity and various metabolic disorders, and acts as an anti-inflammatory protein that inhibits nuclear factor-kappaB activation. The purpose of this study is to clarify the association between the preoperative plasma adiponectin levels and the development of postoperative infection following colorectal cancer surgery.. Peripheral blood samples were collected from 41 colorectal cancer patients before surgery and on postoperative days (PODs) 1, 3, 5, and 7. Plasma adiponectin, leptin, and serum C-reactive protein (CRP) levels were measured and the white blood cells (WBCs) were counted. Subcutaneous and visceral fat volumes were quantified by preoperative CT scans. The patients were divided into a group with postoperative infections and an uninfected group.. In both groups, the postoperative plasma adiponectin levels decreased transiently and then gradually recovered. However, the infected group had significantly lower adiponectin levels throughout the perioperative period than the uninfected group. Logistic regression analysis revealed that preoperative adiponectin level was an independent risk factor for postoperative infection.. Preoperative adiponectin levels may be useful for anticipating the development of postoperative infection following colorectal cancer surgery.

Topics: Adiponectin; Aged; Bacterial Infections; Biomarkers; C-Reactive Protein; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Male; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Preoperative Period; Retrospective Studies; Risk Factors

To study the association of the changes of serum insulin, insulin-like growth factor (IGF-1), insulin-like growth factor binding proteins(IGFBPs), body mass index (BMI), waist and hip circumference ratio(WHR) with the genesis of colorectal cancer.. Sera from 244 colorectal cancer patients before operation, 371 patients after operation and 150 healthy subjects were assayed for insulin, leptin, IGF-1, IGFBP-1 and IGFBP-3 by the enzyme-linked immunosorbent assay. SPSS 13.0 statistics software was applied to analyze the data.. The serum levels of insulin, IGF-1 and the ratio of IGF-1/ IGFBP-3 in colorectal cancer patients before and after surgical treatment were significantly higher than those in controls. The serum levels of IGFBP-3 in patients before and after operation were significantly lower than those in controls, and the differences were significant(P=0.015,P=0.001, respectively). The BMI in colorectal carcinoma patients was not significantly different to the healthy controls(P>0.05). The WHR in colorectal carcinoma patients was higher than that in healthy subjects, and the difference was significant(P=0.003, P=0.035 respectively). The WHR in colon cancer patients was different to that in rectal cancer patients(P=0.046). The WHR and BMI in colon carcinoma patients were positively correlated with the serum insulin level and the value of IGF/IGFBP3. The WHR and BMI were negatively correlated with IGFBP3. The WHR and BMI were not correlated with IGF-1 and IGFBP1.. The serum insulin, IGF-1 levels and the value of IGF-1/IGFBP-3 are significantly increased in colorectal cancer patients, and serum IGFBP-3 level is markedly decreased, which may be related to the genesis of colorectal cancer, but are not correlated with the progress and improvement of colorectal cancer. Central adipositas may be a risk factor for the genesis of colon cancer.

Topics: Adult; Aged; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Risk Factors; Waist-Hip Ratio

Both leptin and vascular endothelial growth factor (VEGF) are growth and angiogenic cytokines that are upregulated in different types of cancer and have been implicated in neoplastic progression. Here we investigated the molecular mechanism by which leptin and VEGF expression are regulated in colon cancer by epidermal growth factor (EGF). In colon cancer cell line HT-29, EGF induced the binding of signal transducer and activator transcription 3 (STAT3) to STAT3 consensus motifs within the VEGF and leptin promoters and stimulated leptin and VEGF mRNA and protein synthesis. All these EGF effects were significantly blocked when HT-29 cells were treated with an inhibitor of the phosphoinositide 3-kinase (PI3K) pathway, LY294002, or with small interfering RNA (siRNA) targeting STAT3. Thus, our study identified the EGF/PI3K/STAT3 signaling as an essential pathway regulating VEGF and leptin expression in EGF-responsive colon cancer cells. This suggests that STAT3 pathways might constitute attractive pharmaceutical targets in colon cancer patients where anti-EGF receptor drugs are ineffective.

Topics: Cell Nucleus; Colorectal Neoplasms; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Gene Silencing; HT29 Cells; Humans; Leptin; Neovascularization, Physiologic; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Protein Binding; RNA, Messenger; STAT3 Transcription Factor; Up-Regulation; Vascular Endothelial Growth Factor A

We investigated the role of leptin receptor (Ob-R) and its relationship with phosphatidylinositol 3-kinase (PI3K)/AKT activation in colorectal carcinomas (CRCs) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC that ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin (Ob) and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of Ob on human CRC cell lines Caco-2, HT-29 and SW-840 and the role of PI3K/AKT-signaling pathway in mediating these actions. Then the expression of Ob-R and its relationship with clinicopathological features was analyzed in 448 CRC, 229 normal colon mucosa and 24 colorectal adenomas using tissue microarray technology. Treatment with Ob resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT-signaling pathway. Pretreatment with Ob-R small interfering RNA or PI3K inhibitor inhibited these responses. Ob-R was significantly overexpressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with Ob expression, early stage and well-differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival (P = 0.0098). Ob plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.

Topics: Adenoma; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Intestinal Mucosa; Leptin; Male; Neoplasm Staging; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Saudi Arabia; Signal Transduction; Survival Analysis

Adipokines may significantly influence the growth and proliferation of tumor stroma and malignant cells within. Reduced adiponectin and increased leptin serum levels were found in colorectal cancer (CRC) patients. Recently, it has been demonstrated that tumor necrosis factor-alpha (TNF-alpha) is able to induce dose-dependent changes in serum adipokine levels. Thus, aims of this study were to evaluate the possible associations between adipokines, TNF-alpha and clinicopathological variables of CRC patients and to analyze their possible prognostic value in predicting relapse-free and overall survival.. Baseline leptin, adiponectin and TNF-alpha levels were analyzed in 90 patients with histologically diagnosed primary or newly diagnosed metastatic CRC treated at 'Tor Vergata' Clinical Center and followed up for a median period of 3 years.. Serum leptin levels were higher in CRC patients than in controls (p<0.0001). Conversely, serum adiponectin levels were lower in CRC patients than in controls (p<0.0001). Leptin inversely correlated with adiponectin (p<0.005). The leptin/adiponectin (L/A) ratio was eight-fold greater in CRC compared to controls (p<0.0001). Kaplan-Meier analysis of relapse-free and overall survival time showed that the L/A ratio was an independent predictor for adverse outcome in CRC.. Serum adipokine levels might have a role in the biology of CRC and the combined measurement of leptin and adiponectin levels might provide useful prognostic information in the management of patients with CRC.

Topics: Adiponectin; Adult; Aged; Case-Control Studies; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Peritoneal Neoplasms; Prognosis; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

We have shown that ObRb, the leptin receptor, is overexpressed in colorectal cancer cells, and that this may influence the patients' outcome. We investigated colonocytes as leptin targets and characterized their pivotal role in antitumor immune response. Cytokine and chemokine mRNAs in HT29 cells were measured by targeted arrays. In vitro, normal colonocytes and human colon cancer cells (HT29, Caco-2, SW480, and HCT116) were used to investigate ObRb transduction system and cytokine releases. Animal colonocytes and CD8 splenocytes and human HT29, HCT116, and CD8(+) cells from blood donors were used to investigate the lymphocyte response to the colonocytes when stimulated by leptin. Leptin-induced cytokine releases in the normal colonic mucosa and tumor growth and cytokine releases within tumors in vivo were measured in male rats and nude mice, respectively. Statistical analysis was done by Fisher's exact and Mann-Whitney U tests. Various cytokines and their receptors were produced in normal and tumoral colonocytes in response to leptin by increasing nuclear factor-kappaB activation. Interleukin-8 (IL-8) was the main cytokine produced in vitro. The levels of IL-8 and its receptor, CXCR1, were higher in tumors than in homologous normal mucosa. Systemic leptin enhanced the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8(+) T cells in vitro. Leptin triggers an inflammatory response in tumor tissue by directly stimulating colonocytes, which can recruit T cytotoxic cells in the tumor microenvironment.

Topics: Aged; Animals; Cell Line, Tumor; Colon; Colorectal Neoplasms; Enterocytes; Female; Humans; Interleukin-8; Leptin; Male; Mice; Mice, Inbred BALB C; Middle Aged; NF-kappa B; Rats; Receptors, Leptin

To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.. We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m(-2)), hypertension (blood pressure > or =140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose > or =6.1 mmol l(-1) or post-load glucose in capillary plasma > or =8.9 mmol l(-1)).. None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20-5.52; P (trend)=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1-9 were 1.56 (95% CI 0.93-2.62; P=0.090), 1.83 (95% CI 1.00-3.36; P=0.051) and 1.50 (95% CI 0.83-2.71; P=0.18), respectively.. Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Colorectal Neoplasms; Epidemiologic Methods; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Sweden

Leptin is elevated in obesity and has been suggested to increase the risk of colorectal cancer (CRC), although the evidence is conflicting. The objective of this study was to compare the susceptibility to colon carcinogenesis of db/db mice that have highly elevated circulating leptin and leptin-deficient ob/ob mice, both of which are obese. Seven-week-old male ob/ob, db/db, and WT mice received 4 weekly i.p. injections of 5 mg/kg azoxymethane (AOM) and were killed 14 wk later for the analysis of putative preneoplastic aberrant crypt foci (ACF). There were no differences in ACF number or multiplicity between ob/ob and db/db mice. Leptin has been shown to induce CYP2E1, the main enzyme that activates AOM, but we observed no differences in hepatic CYP2E1 activity or colonic CYP2E1 protein levels between ob/ob and db/db mice. We also induced ACF with 2 oral doses 3 d apart of 30 mg/kg methylnitrosourea (MNU), a direct-acting carcinogen. There were no differences in ACF number or multiplicity between the two groups of obese animals 5 wk following the last dose of MNU. The colonic mucosa of db/db mice expressed significantly lower mRNA levels of ObRa, the predominant short form of the leptin receptor, compared to ob/ob mice, and following i.p. injection with 1 mg/kg recombinant mouse leptin, exhibited significantly reduced p44/42 pMAPK compared to saline-treated controls. These results show that ObRa is functionally active in the colons of db/db mice. We conclude that leptin does not play a significant role in ACF development.

Topics: Animals; Carcinogens; Colorectal Neoplasms; Cytochrome P-450 CYP2E1; Genetic Predisposition to Disease; Leptin; Methylnitrosourea; Mice; Mice, Inbred C57BL; Mice, Obese; Microsomes; Promoter Regions, Genetic; Receptors, Leptin

Topics: Colorectal Neoplasms; Humans; Leptin; Obesity; Signal Transduction

The obesity hormone, leptin, has been found to play a role in development and proliferation of normal and malignant tissues. Leptin activity is mediated through the leptin receptor (ObR) that is often expressed in different human cancer cells. Previously, we found that the expression of leptin and ObR can be stimulated by hypoxia-mimetic agents. The aim of this study was to analyze the abundance of and relationships among leptin, ObR and hypoxia-inducible factor-1alpha (HIF-1alpha, transcriptional regulator) in human colorectal cancer.. We investigated the expression of leptin, ObR and HIF-1alpha in colorectal cancer specimens from 135 patients who underwent curative resection.. Immunoreactivity for leptin, ObR and HIF-1alpha protein was observed in 69 of 135 (51.1%), 129 of 135 (95.5%) and 88 of 135 (65.2%) of colorectal cancers, respectively. Statistically significant positive correlations were noted between leptin and HIF-1alpha (P = 0.005, r = 0.243), ObR and HIF-1alpha (P < 0.001, r = 0.325) as well as leptin and ObR (P < 0.001, r = 0.426) in the group of all patients as well as in various subgroups depending on clinicopathological features.. The results indicate that the leptin system is overexpressed in human colorectal cancer and this overexpression appears to be associated with the abundance of HIF-1alpha.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Male; Middle Aged; Obesity; Receptors, Cell Surface; Receptors, Leptin; Up-Regulation

Leptin is an adipocyte-derived neurohormone, high levels of which are found in obese individuals. Leptin controls energy expenditure, acting in the brain, and regulates different processes in peripheral organs. Recent studies have suggested that leptin may be involved in cancer development and progression.. To analyse leptin expression in human colorectal cancer as well as in colorectal mucosa and colorectal adenomas.. Leptin expression was assessed by immunohistochemistry in 166 colorectal cancers, 101 samples of colorectal mucosa and 41 adenomas. Leptin concentration in colorectal cancer was correlated with selected clinicopathological features.. Immunoreactivity for leptin was observed in 51.2% (85/166) of primary colorectal cancers. In adenomas leptin expression was observed in 14.6% (6/41) of studied cases. In normal mucosa, leptin was present at low levels, except in tumour bordering areas where its concentration appeared to reflect levels in the adjacent cancer tissue. Leptin expression in colorectal cancer significantly correlated with tumour G2 grade (p = 0.002) as well as with histological type (adenocarcinoma) of tumours (p = 0.044).. Results indicate that leptin is overexpressed in human colorectal cancer, which suggests that the hormone might contribute to colorectal cancer development and progression.

Topics: Adenocarcinoma; Adenoma; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Leptin; Male; Middle Aged

Obesity has been shown to be associated with an increased risk of both colorectal cancer and adenomatous polyps. One mechanism underlying this relationship may involve the growth-promoting effects of the circulating hormones associated with obesity, such as leptin. We conducted a gastroenterology clinic-based, case-control study to evaluate the relationship between circulating leptin concentrations and colorectal adenoma risk; in addition, we evaluated the relationship between leptin receptor polymorphisms and adenoma risk. Individuals with adenomas (n = 157) and colonoscopy-negative controls (n = 191), who had a clinically indicated colonoscopy, were recruited from a large health maintenance organization in the Seattle metropolitan area from 1999 to 2003. Odds ratios and 95% confidence intervals were obtained using logistic regression, adjusting for age at diagnosis, body mass index, family history of colorectal cancer, smoking history, nonsteroidal anti-inflammatory drug use, physical activity, and, among women, menopausal status and postmenopausal hormone use. Among men, those in the highest tertile of leptin concentrations had a 3.3-fold (95% confidence interval, 1.2-8.7) increased adenoma risk compared with those in the lowest tertile (P trend = 0.01). There were no associations between leptin concentrations and adenoma risk in women. There were no associations of leptin receptor genotypes or haplotypes and adenoma risk. The results of this study suggest that, in men, leptin may be associated with risk of colorectal adenomas.

Topics: Adenoma; Adult; Aged; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Genotype; Haplotypes; Humans; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Precancerous Conditions; Receptors, Leptin; Risk Factors; Sex Factors

To elucidate whether leptin is involved in the etiology of female colorectal cancer.. A case-control study nested in the Japan Collaborative Cohort Study. We compared serum leptin levels in 58 cases of female colorectal cancer with those in 145 controls matched for study area and age. Data were analyzed using a conditional logistic regression model with adjustments for known risk factors for the development of colorectal cancer. Quintile cutoff points were determined on the distribution of leptin levels in cases and controls combined.. Serum geometric mean levels of leptin were 6.88 ng/ml in cases and 6.00 ng/ml in controls. The odds ratios of female colorectal cancer risk were 1.40 (95% confidence interval, CI: 0.41-4.78) for the category of the second and third quintiles combined, and 4.84 (CI: 1.29-18.1) for the category of the fourth and fifth quintiles combined relative to the first quintile after adjustment for body mass index (BMI), life-style factors, reproductive factors, and hormonal variables including insulin-like growth factor and its binding protein.. Our results suggest that leptin most likely increases the risk of female colorectal cancer substantially independent of BMI.

Topics: Adult; Aged; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Japan; Leptin; Life Style; Male; Middle Aged; Prospective Studies; Risk Factors

Obesity, a risk factor for colorectal cancer, is associated with elevated serum levels of leptin, the adipocyte-derived hormone, and insulin. Experimental and epidemiologic studies have indicated a role for insulin in the pathogenesis of colon cancer, and recent experimental studies have suggested a similar role for leptin. In a case-control study nested in the Janus Biobank, Norway, we measured serum levels of leptin and C-peptide (a marker of pancreatic insulin secretion) in cryopreserved prediagnostic sera from men (median age, 45 years) who were diagnosed with cancer of the colon (n = 235) or rectum (n = 143) after blood collection (median time, 17 years), and among 378 controls matched for age and date of blood collection. Conditional logistic regression analyses showed an approximately 3-fold increase in colon cancer risk with increasing concentrations of leptin up to an odds ratio (OR) of 2.72 (95% CI = 1.44-5.12) for top vs. bottom quartile (p(trend) = 0.008). The corresponding OR for C-peptide was 1.81 (95% CI = 0.67-4.86; p(trend) = 0.19). The risk estimates remained unchanged after mutual adjustment. No association of hormone levels with rectal cancer risk was found. Reproducibility of hormone measurements assessed by intraclass coefficients (ICCs) for paired samples taken 1 year apart was high for leptin (ICC = 0.82) but lower for C-peptide (ICC = 0.30). Our results suggest that leptin is a risk factor for colon cancer, and that leptin may provide a link between obesity and colon cancer. Leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity-induced adverse endocrine environment. Only weak support for an association of insulin with colon cancer was found.

Topics: Adult; C-Peptide; Case-Control Studies; Colonic Neoplasms; Colorectal Neoplasms; Cryopreservation; Humans; Insulin; Leptin; Logistic Models; Male; Middle Aged; Obesity; Odds Ratio; Registries; Time Factors

Leptin is a protein produced by fat tissue. It has many regulatory effects in the area of energetic metabolism, immunity and haematopoiesis. Its role in tumour diseases especially in states with cachexia is studied. Its physiological diurnal rhythm is very well known. There is lack of information about diurnal rhythm of leptin in tumour diseases except some endocrine tumours. In this study 10 patients with breast and colorectal cancer without marks of kachexia and mostly without pre-existing chemotherapy were examined. The diurnal rhythm of leptin was preserved in cancer patients (morning minimum 10.5 +/- 4.2 ng/ml and nocturnal maximum 17.9 +/- 10.1 ng/ml). The difference between males and females (p < 0.01) and correlation of concentrations of leptin with BMI (r = 0.61, p < 0.001) were preserved too. Basal concentrations of leptin were not different from values of healthy blood donors (10.2 +/- 4.3 ng/ml). Maybe preservation of diurnal rhythm of leptin can be important in planning of cytostatic and immunomodulatory therapy in future.

Topics: Breast Neoplasms; Circadian Rhythm; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged

Serum leptin level is associated with appetite and energy expenditure in healthy individuals. We aimed to evaluate the serum leptin concentration and the other factors which may be associated with weight loss in patients with advanced gastrointestinal cancer.. Forty-four patients with advanced gastrointestinal cancer (25 gastric and 19 colorectal cancer) and 25 healthy controls were enrolled. Serum leptin levels were measured as ng/ml via enzyme linked immuno-sorbent assay (ELISA) method in all subjects. The difference in serum leptin concentration between cancer and control group, the factor associated with its serum level and the relationship between serum leptin concentration and weight loss was evaluated.. Serum leptin concentration of cancer group was significantly lower than controls (p = 0.002). Female subjects had significantly higher serum leptin concentration than male subjects in control group (p = 0.01), while not in cancer group (p > 0.05). Serum leptin concentration was significantly related with gender in controls (p = 0.023, beta = 0.479), while no gender difference was observed in cancer group (p > 0.05). No relationship was found between serum leptin concentration and weight loss percentage in cancer group in linear regression analysis (p > 0.05). No significant difference was observed in serum leptin concentrations between colon and gastric cancer sub-groups (p > 0.05).. Independently from the site of gastrointestinal tract, serum leptin concentration in advanced gastrointestinal cancer is lower than controls and it is not a determinant factor in weight loss. In contrast to healthy subjects, gender does not effect the serum leptin concentration in patients with advanced gastrointestinal cancer.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Reference Values; Regression Analysis; Sex Distribution; Stomach Neoplasms; Weight Loss

Leptin and its relationship with energy metabolism in male weight-stable patients with colorectal liver metastases (n=14) was assessed at baseline and after 6 weeks. At baseline, median leptin concentration was 5.9 microg/l and the median percentage fat mass was 32.1%. Circulating leptin concentrations were correlated with measured percentage fat mass at baseline (r(s)=0.519, P=0.040) and with the changes after 6 weeks (r(s)=0.611, P=0.027) but not with insulin, cortisol, C-reactive protein, appetite or resting energy expenditure. Therefore, it would appear that leptin concentrations reflect changes in fat mass in male weight-stable patients with cancer and their role in the regulation of energy metabolism appears more complex than previously proposed.

Topics: Adenocarcinoma; Adipose Tissue; Adult; Aged; Appetite; Body Composition; Body Weight; C-Reactive Protein; Colorectal Neoplasms; Energy Metabolism; Humans; Hydrocortisone; Insulin; Leptin; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Serum Albumin

Leptin is a hormone and acute phase reactant with multiple effects during both rest and inflammatory period. Effects of leptin in acute phase response cover a modulation of hypothalamo-pituitoadrenal (HPA) axis, too. In our study we evaluate the dynamics of leptin and glucocorticoid acute changes in model situations of infectious and non-infectious inflammatory reaction.. This study was realized on a group of patients 1--after operation of carcinoma coli (16 persons), 2--after laparoscopic non-adjustable gastric banding (13 persons), and patients 3--with development of postoperative intraabdominal sepsis (22 persons). Plasma levels of leptin, ACTH, cortisol, TNF-alpha, IL-6, C reactive protein (CRP), and alpha1-antitrypsin (AAT) were measured from -7 to +3 day related to surgery or 2nd day after a day when signs of sepsis were occurred.. All tested parameters responded to surgical trauma with elevation 12 h after operation except leptin that elevated +24 h after surgery. Maximal levels of measured parameters were found 12 h after surgery (for cortisol), 24 h after surgery (for leptin, TNF-alpha, IL-6), or 36 h after operation (for CRP and AAT). Maximal levels of cortisol after a resection of coli or maximal levels of leptin after laparoscopic gastric banding fall to septic range. Other parameters in uncomplicated postoperative period significantly differed from septic levels on p < 0.01. There wasn't found statistically significant correlation between leptin and cortisol or between leptin and ACTH in all groups.. The elevation of leptin in postoperative period and during sepsis reflects a different regulation of this protein in rest period and during systemic inflammatory response. The inhibitory effect of leptin to HPA axis during stress response was documented in vitro, however, its physiological importance is not clear, yet. Our study didn't prove a statistically significant relation between plasma cortisol and leptin. The different dynamics of leptin and cortisol after surgical trauma shows that both factors have own specific regulation.

Topics: Acute-Phase Reaction; Adrenocorticotropic Hormone; Adult; Aged; alpha 1-Antitrypsin; C-Reactive Protein; Colorectal Neoplasms; Gastroplasty; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Sepsis; Stress, Physiological; Surgical Procedures, Operative; Tumor Necrosis Factor-alpha

Patients with cachexia suffer from anorexia, weight loss and hypermetabolism. This study examined the relationship between plasma leptin concentration, leptin gene expression, weight loss and the acute-phase response in a group of surgical patients.. Body composition, plasma leptin, interleukin (IL) 6, soluble tumour necrosis factor receptor (sTNF-R) 55, sTNF-R75 and C-reactive protein were analysed in a cohort of 28 patients undergoing elective surgery. Subcutaneous and omental leptin messenger RNA (mRNA) was analysed in a subgroup of 14 patients.. After adjustment for fat mass (FM), a significant partial correlation coefficient was found between plasma leptin and serum IL-6 concentration (P = 0.037). A positive correlation was found only between plasma leptin and omental leptin mRNA (P = 0.009). Patients with an acute-phase response had a significantly higher level of plasma leptin per unit FM (P = 0.049). Stepwise multiple regression showed that FM (P < 0.0005) and serum IL-6 (P = 0.018) were independent predictors of plasma leptin level.. Plasma leptin levels appear to be influenced by proinflammatory cytokines. Omental fat may have more influence on plasma leptin than subcutaneous fat. Accelerated weight loss in patients with cancer with an ongoing inflammatory response could be mediated in part by inappropriately high plasma levels of leptin.

Topics: Acute-Phase Reaction; Aged; Aged, 80 and over; C-Reactive Protein; Colorectal Neoplasms; Diverticulum, Colon; Elective Surgical Procedures; Etanercept; Female; Humans; Immunoglobulin G; Interleukin-6; Leptin; Male; Middle Aged; Omentum; Receptors, Leptin; Receptors, Tumor Necrosis Factor; RNA, Messenger; Weight Loss

In addition to its basic role as regulator of the amount of body fat and food intake leptin plays a part also as an acute phase reactant. A rise of the leptin level during this period may be associated with anorexia and cachexia in relation to general inflammatory manifestations. The objective of the present study was to characterize the dynamics of the leptin concentration in patients after intraabdominal surgery.. The prospective study was implemented in a group of 16 men subjected to planned surgery--resection of colorectal carcinoma. The plasma leptin concentration (RIA), TNF alpha, IL-beta. IL-6, sIL-2R (ELISA), CRP, alpha-1-antitrypsin, alpha-1-acid glycoprotein and ceruloplasmin (nephelometry) were assessed before surgery and then +24, +48 and +72 hours after the beginning of the operation and compared with concentrations in healthy subjects.. Plasma leptin concentrations culminate +24 hours after surgery and in this stage they do not correlate with the BMI. Within 48 hours the concentration reaches rapidly normal levels. TNF alpha, IL-6 and sIL-2R reach maximal levels 24-48 hours after the onset of surgery with a subsequent slow decline. All acute phase proteins (APP) have prolonged dynamics with an elevation within +72 hours. A significant correlation was proved between the leptin concentration and TNF alpha 24 hours after surgery (r = 0.43, p < 0.05) and between leptin and IL-6 24 hours after surgery (r = 0.32, p < 0.05).. The dynamics of the plasma leptin concentration during the postoperative period differ from the typical development of early indicators of the systemic inflammatory response--cytokines as well as from the dynamics of APP. Leptin elevation during this period may contribute to anorexia of patients after major surgery. However, rapid normalization of the level within 48 hours after surgery indicates however that leptin is involved also in other, so far unspecified factors with an anorectic action.

Topics: Abdomen; Acute-Phase Proteins; Aged; Colorectal Neoplasms; Humans; Interleukins; Leptin; Male; Middle Aged; Prospective Studies; Tumor Necrosis Factor-alpha

Leptin is a hormone which controls fat metabolism. Leptin plasma levels and adipose tissue mRNA expression were measured in cancer patients. Plasma levels were correlated with TNM staging, cachexia parameters, tumour markers and hormones. Breast and colorectal cancer patients showed blood plasma levels of insulin, TNF-alpha and tumour markers higher than controls. Breast cancer patients, but not colorectal cancer patients, had plasma levels and adipose tissue expression of leptin significantly higher than controls associated with elevated values of estrogen- and progesterone-receptors. These data suggest the possible use of leptin as a clinical marker.

Topics: Adenocarcinoma; Adipose Tissue; Adult; Aged; Biomarkers, Tumor; Blotting, Northern; Breast Neoplasms; Colorectal Neoplasms; Female; Gene Expression; Humans; In Situ Hybridization; Leptin; Male; Middle Aged; Neoplasm Staging; Radioimmunoassay; RNA, Messenger; Tumor Necrosis Factor-alpha

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes, thus protecting them from lipotoxicity. The fact that TG content in nonadipocytes normally remains within a narrow range, while that of adipocytes varies enormously with food intake, is consistent with a system of TG homeostasis in normal nonadipocytes. The facts that when leptin receptors are dysfunctional, TG content in nonadipocytes such as islets can increase 100-fold, and that constitutively expressed ectopic hyperleptinemia depletes TG, suggest that leptin controls the homeostatic system for intracellular TG. The fact that the function and viability of nonadipocytes is compromised when their TG content rises above or falls below the normal range suggests that normal homeostasis of their intracellular TG is critical for optimal function and to prevent lipoapoptosis. Thus far, lipotoxic diabetes of fa/fa Zucker diabetic fatty rats is the only proven lipodegenerative disease, but the possibility of lipotoxic disease of skeletal and/or cardiac muscle may require investigation, as does the possible influence of the intracellular TG content on autoimmune and neoplastic processes.

Topics: Adipocytes; Aged; Animals; Cell Transformation, Neoplastic; Colorectal Neoplasms; Diabetes Mellitus; Diabetes Mellitus, Type 1; Energy Intake; Fatty Acids; Fatty Acids, Nonesterified; Homeostasis; Humans; Islets of Langerhans; Leptin; Liver Diseases; Models, Biological; Obesity; Proteins; Rats; Rats, Zucker; Risk Factors; Triglycerides