leptin and Adenocarcinoma

Esophageal adenocarcinoma is a cancer with poor prognosis, and its incidence has risen sharply over recent decades. Obesity is a major risk factor for developing this cancer and there is a clear male gender bias in the incidence that cannot be fully explained by known risk factors. It is possible that a difference in the expression of estrogen, or its signaling axes, may contribute to this gender bias. We undertook a comprehensive literature search and analyzed the available data regarding estrogen and estrogen receptor expression, and the possible sex-specific links with esophageal adenocarcinoma development. Potentially relevant associations between visceral vs subcutaneous fat deposition and estrogen expression, and the effect of crosstalk between estrogen and leptin signaling were identified. We also found limited studies suggesting a role for estrogen receptor β expression in esophageal adenocarcinoma development. The current literature supports speculation on an etiological role for estrogen in the male gender bias in esophageal adenocarcinoma, but further studies are required.

Topics: Adenocarcinoma; Adipose Tissue; Esophageal Neoplasms; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Humans; Leptin; Male; Sex Factors; Signal Transduction

To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development.. A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance [HOMA]). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value.. Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 [95% CI -7.5, -1.4] cm; p < 0.01). Effects on primary outcomes were not statistically significant.. This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment.. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257.

Topics: Adenocarcinoma; Adiponectin; Barrett Esophagus; C-Reactive Protein; Case-Control Studies; Esophageal Neoplasms; Exercise; Humans; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Overweight; Risk Factors; Tumor Necrosis Factor-alpha

Current molecular characterization of pancreatic ductal adenocarcinoma (PDAC) does not incorporate the host reaction to cancer cells and cannot predict the response to chemo- or immunotherapy. Leptin is an adipokine involved in regulating energy balance with a possible role in the development of obesity-associated cancers, but its relationship with other pathways in pancreatic carcinogenesis has not been established yet. The aim of this prospective study was to assess the involvement of leptin and phosphoinositide 3-kinase (PI3K) in the survival of overweight and/or diabetic patients with PDAC.. A total of 112 patients were included, 56 diagnosed with PDAC and 56 age and sex-matched healthy controls, with a maximum follow-up of 24-months. The circulating leptin, interleukin 1-beta, tumor factor necrosis-alpha, and PI3K were measured by enzyme-linked immunosorbent assay (ELISA). A multivariate Cox regression model was used to determine the factors influencing survival.. The serum levels of leptin [38.5 (31.6-47.0) pg/ml] and other cytokines in PDAC patients were similar to controls, irrespective of the presence of diabetes. No significant correlation between the biomarkers was found. In obese and overweight patients, the leptin level and survival rate were lower than in non-obese patients.. The leptin level was not associated with the presence of PDAC, although it was lower in obese and overweight patients who had lower survival. No association with inflammatory biomarkers or PI3K was noted. Furthermore, leptin levels had no independent role in survival, suggesting that the prognostic role of obesity in PDAC is based on a different pathway.

Topics: Adenocarcinoma; Biomarkers; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Diabetes Mellitus; Humans; Leptin; Obesity; Overweight; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Prognosis; Prospective Studies

Topics: Adenocarcinoma; Animals; Carcinogenesis; Cell Proliferation; Gastric Mucosa; Hyperplasia; Leptin; Male; Methylnitronitrosoguanidine; Rats; Rats, Sprague-Dawley; Stomach; Stomach Neoplasms

Topics: Adenocarcinoma; Adenoviridae; Aging; Animals; Antibodies, Monoclonal; Cell Line, Tumor; CTLA-4 Antigen; Diet; Disease Models, Animal; Female; Humans; Immunity; Immunotherapy; Kidney Neoplasms; Leptin; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Obesity; Oligodeoxyribonucleotides; Receptors, Fc; Receptors, Leptin; Recombinant Fusion Proteins; TNF-Related Apoptosis-Inducing Ligand

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

Esophageal adenocarcinoma (EAC) is one of the most common malignancies in the world which is associated the increased prevalence of obesity. In the context of obesity, leptin can directly contribute to progression of EAC. Adiponectin inhibits leptin-induced oncogenic signaling in EAC cells. However, the exact molecular mechanisms linking obesity, adipokines, and EAC remain far from completely understood. In the present study, we tested the role of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) in adiponectin-induced protective effects against leptin-induced EAC cell proliferation. We found that globular adiponectin (gAD) significantly inhibited leptin-induced increase of cell proliferation and decrease of apoptosis in OE 19 cells. Moreover, leptin-induced increase of UHRF1 expression was suppressed by gAD. Compared with normal controls, UHRF1 expression was markedly increased in EAC tissues and cell lines. Silence of UHRF1 increased the expression of cleaved caspase 3 and 9 and Bax, reduced the expression of Bcl-2, promoted apoptosis, and inhibited cell proliferation in OE 19 cells. Overexpression of UHRF1 significantly blocked gAD-induced decrease of cell proliferation and increase of apoptosis in leptin-treated cells. Silence of adiponectin receptor 1/2 (AdipoR1/2) could inhibit gAD-induced decrease of cell proliferation and increase of apoptosis in leptin-treated cells. Silence of AdipoR2, but not AdipoR1, suppressed gAD-induced decrease of UHRF1 expression in leptin-treated cells. The results indicated that gAD inhibited the prooncogenic effects of leptin via AdipoR2-mediated suppression of UHRF1. Our study provides novel insights into the role of UHRF1 in the development of EAC and the mechanism of antitumor effect of gAD.

Topics: Adenocarcinoma; Adiponectin; CCAAT-Enhancer-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Esophageal Neoplasms; Humans; Leptin; Neoplasm Proteins; Receptors, Adiponectin; Ubiquitin-Protein Ligases

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

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

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

Obesity is a well-known risk factor for breast cancer development in postmenopausal women. High insulin and leptin levels seem to have a role modulating the growth of these tumours. Sam68 is an RNA-binding protein with signalling functions that has been found to be overexpressed in breast cancer. Moreover, Sam68 may be recruited to insulin and leptin signalling pathways, mediating its effects on survival, growth and proliferation in different cellular types. We aimed to study the expression of Sam68 and its phosphorylation level upon insulin and leptin stimulation, and the role of Sam68 in the proliferative effect and signalling pathways that are activated by insulin or leptin in human breast adenocarcinoma cells. In the human breast adenocarcinoma cell lines MCF7, MDA-MB-231 and BT-474, Sam68 protein quantity and gene expression were increased upon leptin or insulin stimulation, as it was checked by qPCR and immunoblot. Moreover, both insulin and leptin stimulation promoted an increase in Sam68 tyrosine phosphorylation and negatively regulated its RNA binding capacity. siRNA was used to downregulate Sam68 expression, which resulted in lower proliferative effects of both insulin and leptin, as well as a lower activation of MAPK and PI3K pathways promoted by both hormones. These effects may be partly explained by the decrease in IRS-1 expression by down-regulation of Sam68. These results suggest the participation of Sam68 in both leptin and insulin receptor signaling in human breast cancer cells, mediating the trophic effects of these hormones in proliferation and cellular growth.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Female; Humans; Insulin; Insulin Receptor Substrate Proteins; Leptin; Phosphorylation; RNA-Binding Proteins; Signal Transduction

Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27-7.16; P

Topics: Adenocarcinoma; Biomarkers, Tumor; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Leptin; Male; Middle Aged; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors; Sex Characteristics

Antiangiogenic treatment is at the horizon in the palliative treatment of gastric cancer (GC), but data on proangiogenic biomarkers are still limited. The aim of this study was to analyze five proteins with a function in tumor angiogenesis: vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), follistatin, leptin, and platelet endothelial cell adhesion molecule 1 (CD31) in peripheral blood and corresponding tumor tissue.. From 2008-2010, tumor tissue (n = 76) and corresponding preoperative serum (n = 69) of patients with localized GC were collected; 45 had perioperative chemotherapy. Protein serum or tumor lysate levels of these factors were measured by an angiogenesis multiplex immunoassay and correlated with response and survival.. Serum Ang-2 had prognostic relevance in the whole study population (P = 0.027). In subgroup analysis, serum VEGF and Ang-2 had prognostic relevance in primarily resected patients (P = 0.028; P = 0.048) but no association was found in neoadjuvantly treated patients. Follistatin concentration in the tumor tissue was associated with prognosis in all patients (P = 0.019). Tumor VEGF concentrations were correlated with histopathologic response (P = 0.011), with patients showing >50% remaining tumor having higher VEGF concentrations. The tissue Ang-2/VEGF ratio was significantly correlated with both clinical and histopathologic response (P = 0.029, P = 0.009). Additionally, the level of leptin in the tissue was associated with clinical response: nonresponding patients had higher leptin levels than those of responding patients (P = 0.032).. Our results show the importance of angiogenetic factors in serum and tumor tissue in GC for prognosis and treatment response. Further trials in larger patient populations are warranted for a further evaluation of proangiogenetic factors as biomarkers in gastrointestinal cancer.

Topics: Adenocarcinoma; Angiogenic Proteins; Angiopoietin-2; Biomarkers, Tumor; Female; Follistatin; Germany; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Platelet Endothelial Cell Adhesion Molecule-1; Prognosis; Prospective Studies; ROC Curve; Stomach; Stomach Neoplasms; Vascular Endothelial Growth Factor A

Obesity is associated with cancer risk in esophageal adenocarcinoma (EAC). Adipose tissue directly stimulates tumor progression independently from body mass index (BMI), but the mechanisms are not fully understood. We studied the morphological, histological and molecular characteristics of peritumoral and distal adipose tissue of 60 patients with EAC, to investigate whether depot-specific differences affect tumor behavior. We observed that increased adipocyte size (a hallmark of obesity) was directly associated with leptin expression, angiogenesis (CD31) and lymphangiogenesis (podoplanin); however, these parameters were associated with nodal metastasis only in peritumoral but not distal adipose tissue of patients. We treated OE33 cells with conditioned media (CM) collected from cultured biopsies of adipose tissue and we observed increased mRNA levels of leptin and adiponectin receptors, as well as two key regulator genes of epithelial-to-mesenchymal transition (EMT): alpha-smooth muscle actin (α-SMA) and E-cadherin. This effect was greater in cells treated with CM from peritumoral adipose tissue of patients with nodal metastasis and was partially blunted by a leptin antagonist. Therefore, peritumoral adipose tissue may exert a direct effect on the progression of EAC by secreting depot-specific paracrine factors, and leptin is a key player in this crosstalk.

Topics: Actins; Adenocarcinoma; Adipocytes; Adipose Tissue; Aged; Antigens, CD; Cadherins; Cell Size; Culture Media, Conditioned; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Lymphangiogenesis; Lymphatic Metastasis; Male; Membrane Glycoproteins; Middle Aged; Neovascularization, Pathologic; Obesity; Paracrine Communication; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Adiponectin; RNA, Messenger; Signal Transduction; Tissue Culture Techniques; Tumor Cells, Cultured

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

Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.. Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations.. We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin.. In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Growth Processes; Drug Resistance, Neoplasm; Esophageal Neoplasms; Female; Gene Expression Profiling; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Prognosis; RNA, Messenger; Stomach Neoplasms

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

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

Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

Topics: Adenocarcinoma; Animals; Antibodies; Antineoplastic Agents; Carcinogenesis; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Gastric Mucosa; Humans; Injections, Intraperitoneal; Intestinal Mucosa; Leptin; Mice; Mice, Transgenic; Neoplasms, Experimental; Protein Kinases; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Stomach; Stomach Neoplasms; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Individuals with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EA). Obesity contributes to the development of BE and its progression to cancer. We investigated the roles of obesity-induced hyperinsulinemia and dysregulation of adipokines in these processes.. We measured fasting levels of glucose, insulin, leptin, and adiponectin in 392 patients enrolled in the Seattle Barrett's Esophagus Study. We calculated homeostatic model assessment scores (a measure of insulin sensitivity) and identified subjects with metabolic syndrome. We evaluated the association between these measures and the risk of EA using Cox regression models adjusted for known risk factors.. Increasing homeostatic model assessment scores were associated with an increasing risk for EA; the strongest association was observed within the first 3 years after participants entered the study (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.43-4.1; P trend = .001). Leptin level also was associated significantly with an increased risk of EA within 3 years (HR, 2.51; 95% CI, 1.09-5.81; P trend = .03) and 6 years (HR, 2.07; 95% CI, 1.01-4.26; P trend = .048) of baseline. The level of high-molecular-weight adiponectin had a nonlinear inverse association with risk of EA; the strongest associations were observed in the second tertile (HR, 0.34; 95% CI, 0.14-0.82). Metabolic syndrome was not associated with risk of EA.. Among patients with BE, increased levels of leptin and insulin resistance are associated with increased risk for EA, whereas increased levels of high-molecular-weight adiponectin is associated inversely with EA. These biomarkers might be used to determine cancer risk among patients with BE.

Topics: Adenocarcinoma; Adiponectin; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biomarkers; Blood Glucose; Esophageal Neoplasms; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Risk Assessment

Esophageal adenocarcinoma incidence is rapidly increasing which may be due to the growing incidence of Barrett's esophagus (BE) and obesity. The mechanisms linking obesity and progression of Barrett's carcinogenesis is poorly understood. The aim of the study was to evaluate the expression of adipokines receptors in BE and in normal squamous epithelium in the same patients in correlation with obesity parameters.. Expression of adiponectin receptors 1 and 2 protein (AdipoR1, AdipoR2) as well as leptin receptor protein (ObR) in biopsies from 27 BE and normal squamous epithelium (N) in the same patients as well as in obese and normal controls were assessed with Western-blot analysis. These correlations were confirmed with the quantitative RT-PCR (qRT-PCR). AdipoR1 and ObR protein levels were similar in BE mucosa and squamous epithelium in the same patients in Western-blot analysis (2303 vs. 2448 OB units; 106927 vs. 103390, respectively; p>0.05). RT-PCR analysis confirmed this observation for AdipoR1, R2 and ObR genes expression (0.11±0.08 vs. 0.19±0.24, p=0.78; 0.24±0.36 vs. 0.33±0.49, p=0.5375; 0.71±0.8 vs. 1.33±2.95, p=1.0; respectively). Using linear correlation analysis we found the positive correlation between AdipoR1 expression in Barrett's epithelium compared to squamous epithelium in the same patients (N) (r=0.5; p=0.008) and between ObR expression in BE and N (r=0.8; p<0.001). The AdipoR1 and ObR protein levels were significantly higher in BE patients compared to controls and obese controls (2303 vs. 895 vs. 1674 and OD units, p<0.05).. in opposite to the prior hypothesis adiponectin and leptin receptors activation in BE may be not caused by obesity.

Topics: Adenocarcinoma; Adiponectin; Adult; Aged; Barrett Esophagus; Epithelium; Esophageal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Obesity, Abdominal; Receptors, Adiponectin; Receptors, Leptin

To investigate the relationship between the expression of leptin, p-mTOR protein and the pathogenesis, development and clinicopathological features in colon carcinoma.. The expression of leptin and p-mTOR protein was evaluated by immunohistochemical methods in 40 normal colon mucosas, 40 colon adenomatous polyps and 108 cases of colon carcinomas. The relationship between the staining pattern and clinicopathogical features was examined.. The positive rates of detection of leptin in normal colon mucosa, adenomatous polyps and colon carcinomas were 10% (4/40), 27.5% (11/40), and 71.3% (77/108), respectively; with significant differences among the three groups (P<0.05). The positive rates of p-mTOR protein in the normal colon mucosa, the adenomatous polyps, and the colon carcinomas were 2.5% (1/40), 20% (8/40), and 61.1% (66/108), respectively; with significant differences among the three groups (P<0.05). The expression of leptin and p-mTOR proteins were related to invasive depth, TNM stages, lymph node metastasis, distant metastasis and tumor differentiation (P<0.05), but not to age, sex, or site (P>0.05). In colon carcinoma tissues, leptin expression was positively correlated with p-mTOR expression (P<0.01).. Leptin and p-mTOR proteins may play important roles in the occurrence and development of colon carcinoma. The detection of leptin and p-mTOR may be helpful for evaluation of the prognosis of the patient with colon carcinoma.

Topics: Adenocarcinoma; Adenomatous Polyps; Aged; Colon; Colonic Neoplasms; Female; Humans; Intestinal Mucosa; Leptin; Male; Middle Aged; Neoplasm Metastasis; Phosphorylation; Prognosis; TOR Serine-Threonine Kinases

Apigenin, a common edible plant flavonoid, is a well characterised antioxidant. The adipokine leptin exerts proliferative and anti-apoptotic activities in a variety of cell types. In cancer cells, apigenin may induce a pro-apoptotic pathway whereas leptin has an anti-apoptotic role. The purpose of the study is to investigate the role of apigenin and of leptin/leptin receptor pathway on proliferation and on apoptosis in lung adenocarcinoma.. Immunocytochemistry, flow cytometry and RT-q-RT PCR, were used to investigate the expression and modulation of leptin receptors on the lung adenocarcinoma cell line A549 in presence or absence of apigenin and of leptin, alone or combined. Clonogenic test to evaluate cell proliferation was assessed. Exogenous leptin binding to its receptors by flow cytometry, reactive oxygen species (ROS) by dichlorofluorescein diacetate analysis, cell death by ethidium bromide and apoptosis by annexin V analysis were assessed. Apoptosis was assessed also in presence of lung adenocarcinoma pleural fluids (PF) (n=6).. A549 express leptin/leptin receptor pathway and its expression is upregulated by apigenin. Apigenin alone or combined with leptin significantly decreases cell proliferation and significantly increases the spontaneous release of ROS, with augmented cell death and apoptosis, this latter also in the presence of lung adenocarcinoma PF. Leptin alone significantly increases cell proliferation and significantly decreases cell death.. These results strongly suggest the potential utility of the flavonoid apigenin in the complementary therapeutic approach of patients with lung adenocarcinoma.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Apigenin; Apoptosis; Cell Growth Processes; Cell Line, Tumor; Cell Survival; Humans; Leptin; Lung Neoplasms; Receptors, Leptin

Obesity is an established risk factor for endometrial cancer. Leptin, a secreted protein of the ob gene by white adipose tissue, plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic cancer cells. However, a direct role for leptin in endometrial cancer has not been demonstrated. In the present study, the effect of leptin on the proliferation of Ishikawa endometrial cancer cells was investigated as well as the possible mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. The expression of leptin receptor (ObRb) in Ishikawa cells was detected by RT-PCR and Western blotting. The cells after serum starvation, were treated by leptin with various concentrations (0, 10, 50, 100, 150 ng/mL) for different durations (6, 12, 24 h). The effect of leptin treatment on cell proliferation was examined by MTT assay. Meanwhile, inhibitory effect of Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) inhibitor AG490 or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 on the proliferation of Ishikawa cells induced by leptin was also studied. Ishikawa cells were treated with 100 ng/mL leptin for various periods (0, 20, 40, 60 min), and the levels of STAT3 phosphorylation and ERK1/2 phosphorylation were examined by Western blotting. The results showed that leptin induced the phosphorylation of STAT3 and the activation of ERK1/2 in a time- and dose-dependent manner in the Ishikawa endometrial cancer cells. Blocking STAT3 phosphorylation with the inhibitor AG490, or blocking ERK1/2 activation by the specific ERK1/2 kinase inhibitor, PD98059, abolished leptin-induced proliferation of Ishikawa cells. In addition, leptin was found to potently induce the invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of STAT3 (AG490) and ERK1/2 kinase (PD98059). These results suggested that leptin promotes endometrial cancer growth and invasiveness by activating STAT3 and ERK1/2 signaling pathways and therefore blocking its action at the receptor level can be a rational therapeutic strategy.

Topics: Adenocarcinoma; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Enzyme Inhibitors; Female; Flavonoids; Humans; Leptin; MAP Kinase Signaling System; Neoplasm Invasiveness; STAT3 Transcription Factor; Tyrphostins

To assess the expression of HER-2 and leptin in gastric cancer and evaluate their relationship with VEGF expression and clinicopathological features, and their prognostic value for gastric cancer patients.. One hundred and ten gastric cancer specimens and the corresponding metastatic lymph nodes were detected for HER-2 by immunohistochemistry (IHC). All primary cancer tissues were detected for leptin, OB-Rb and VEGF. Ninty-six specimens of normal gastric mucosa served as the control.. The expression level of HER-2, leptin and OB-Rb in gastric cancer tissues were significantly higher than those in normal tissues (19.1% vs. 8.0%, 49.1% vs. 34.0%, and 60.9% vs. 46.0%, P < 0.05). HER-2 overexpression was moderately homogenous in primary gastric cancer and matastatic lymph nodes (P = 0.607, Kappa = 0.581). There was a correlation between the expression of HER-2 and leptin, both of which were significantly correlated with tumor invasion depth, metastatic lymph nodes ratio (NR), distal metastasis, TNM stage and VEGF expression. However, there was no significant correlation between OB-Rb expression and the clinicopathological features evaluated. Cox regression multivariate analysis showed that tumor size, histological grade, NR, stage, chemotherapy and HER-2 expression were independent prognostic factors.. HER-2 is stably expressed in primary gastric cancer and metastatic lymph nodes. HER-2 and leptin play an important role in the progression and angiogenesis of gastric cancer. High expression of HER-2 is a prognostic factor for poor outcome.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Follow-Up Studies; Gastrectomy; Humans; Leptin; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Receptor, ErbB-2; Receptors, Leptin; Stomach Neoplasms; Survival Rate; Tumor Burden; Vascular Endothelial Growth Factor A

Prostaglandins are important in the progression of various gastrointestinal cancers including oesophageal adenocarcinoma (OAC). Cyclo-oxygenase (COX)-2 inhibitors reduce OAC prostaglandin production but also have potentially detrimental effects on vascular endothelial function by reducing prostacyclin production and increasing the risk of cardiovascular events. We have examined the effects of inhibiting microsomal prostaglandin synthase-1 (mPGES-1), the enzyme downstream of COX-2 in the prostaglandin synthetic cascade. In OAC cells, reduction of mPGES-1 with RNA interference blocked PGE2 production, inhibited serum-induced proliferation and enhanced apoptosis in the COX-2 expressing cell lines (OE33 and FLO) but had no effect in COX-2 deficient BIC-1 cells. Three different methods of inhibiting mPGES-1 (RNA interference, a novel small molecule inhibitor and the endogenous inhibitor 15-deoxy-Delta(12,14)-PGJ(2)) also blocked leptin induced mPGES-1 expression and PGE2 production and abolished the leptin-induced proliferative and anti-apoptotic effects in OE33 cells, without affecting COX-2 expression. The anti-proliferative effects were equivalent to those produced by COX-2 inhibitory concentrations of celecoxib and NS-398. However, unlike the two COX-2 inhibitors, mPGES-1 inhibition did not reduce endothelial prostacyclin production. In contrast to the effects of the COX-2 inhibitor celecoxib, mPGES-1 inhibition had no effects on Akt kinase activity in OAC cells. We conclude that inhibition of mPGES-1 has potentially beneficial effects in OAC without the potentially detrimental effects on vascular endothelial prostacyclin synthesis. We have also confirmed that celecoxib has anticancer actions separate from the inhibition of COX-2. Inhibition of mPGES-1 may be therapeutically useful in the treatment and prevention of OAC.

Topics: Adenocarcinoma; Apoptosis; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Endothelial Cells; Epoprostenol; Esophageal Neoplasms; Humans; Intramolecular Oxidoreductases; Leptin; Prostaglandin-E Synthases; Pyrazoles; RNA, Small Interfering; Sulfonamides

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

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

We investigated the association between esophageal cancer and cachexia-anorexia syndrome (CAS) of the alimentary tract and leptin, an adipocytokine crucial for body weight regulation, a modulator of inflammatory/immune response, implication of which in cancer and CAS development remains debatable. Circulating leptin was measured in 135 esophageal cancer patients (51 non-cachectic and 84 cachectic) and 83 controls (63 non-cachectic and 20 cachectic) and referred to cancer stage, CAS, and inflammatory and nutritional indices. Leptin was down-regulated in cancer patients and cachectic controls as compared to non-cachectic controls, with more pronounced hypoleptinemia in advanced cancers. Leptin correlated directly with BMI, TNF-alpha, albumin, and hemoglobin and indirectly with IL-6, IL-8, and hsCRP. The correlations, except for hsCRP, were more pronounced in females. BMI alone (females) and BMI and hsCRP (males) were independent predictors of leptin explaining over 60% of its variability. Following adjustment for BMI and gender, cancer-related CAS but not cancer itself negatively affected leptin. Leptin and BMI were independently associated with cancer-related and non-malignant CAS with diagnostic accuracy of 93% in identifying subjects with CAS. Pro-inflammatory, angiogenic and mitogenic properties of leptin do not seem to be important for esophageal cancer development but hypoleptinemia, independently from co-occurring reduction of adiposity, appears to be strongly associated with esophageal cancer-related CAS and non-malignant CAS of the alimentary tract.

Topics: Adenocarcinoma; Anorexia; Body Mass Index; C-Reactive Protein; Cachexia; Carcinoma, Squamous Cell; Down-Regulation; Esophageal Neoplasms; Female; Gastrointestinal Tract; Hemoglobins; Humans; Inflammation; Interleukin-6; Interleukin-8; Leptin; Male; Serum Albumin; Syndrome; Tumor Necrosis Factor-alpha

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

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

The adipocyte-derived catabolic protein leptin alters cell-mediated immunity and cytokine crosstalk. This may provide new insights into the altered immune response, seen in obese individuals. Therefore, we determined the tissue distribution of immune cells in diet-induced obese (dio) and normal weight F344 rats challenged with MADB106 tumor cells or leptin. Immune cell distribution in blood (by FACS analysis) and tissues (NK cells in spleen and liver, immunohistologically) as well as pro-inflammatory cytokines (IL-6, TNF-α; by flow cytometry) were investigated in 28 normal weight and 28 dio rats (n = 4-6/group). Pro-inflammatory cytokines were increased 3-fold for IL-6 and 7-fold for TNF-α in obese animals. Higher numbers of blood monocytes and NK cells were found in obese as compared to normal weight animals. In dio rats challenged with leptin and MADB106 tumor cells, monocyte numbers were decreased as compared to the obese control animals. Immunohistochemistry revealed an altered NK cell distribution in a compartment-, treatment-, and bodyweight-specific manner. In conclusion, our data reveal a distinct distribution pattern of monocytes and NK cells in dio rats as compared to normal weight littermates and an additional modulatory effect of a leptin- and MADB106 tumor cell challenge.

Topics: Adenocarcinoma; Animals; Body Weight; Female; Flow Cytometry; Inflammation; Interleukin-6; Killer Cells, Natural; Leptin; Male; Mammary Neoplasms, Animal; Monocytes; Neoplasm Transplantation; Obesity, Abdominal; Rats; Rats, Inbred F344; Recombinant Proteins; Tumor Microenvironment; Tumor Necrosis Factor-alpha

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

The prevalence of obesity, an established epidemiologic risk factor for many chronic diseases including cancer, has been steadily increasing in the US over several decades. The mechanisms used to regulate energy balance and adiposity and the relationship of these factors to cancer are not completely understood. Here we have used knockout mice to examine the roles of the transcription factors CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta in regulating body composition and systemic levels of hormones such as insulin-like growth factor-1 (IGF-1), leptin and insulin that mediate energy balance. Dual-energy X-ray absorptiometry showed that C/EBPbeta, either directly or indirectly, modulated body weight, fat content and bone density in both males and females, while the effect of C/EBPdelta was minor and only affected adiposity and body weight in female animals. Levels of IGF-1, leptin and insulin in the serum were decreased in both male and female C/EBPbeta(-/-) mice, and C/EBPbeta was associated with their promoters in vivo. Moreover, colon adenocarcinoma cells displayed reduced tumorigenic potential when transplanted into C/EBPbeta-deficient animals, especially males. Thus, C/EBPbeta contributes to endocrine expression of IGF-1, leptin and insulin, which modulate energy balance and can contribute to cancer progression by creating a favorable environment for tumor cell proliferation and survival.

Topics: Adenocarcinoma; Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Protein-delta; Cell Division; Colonic Neoplasms; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Obesity

In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia.

Topics: Adenocarcinoma; Animals; Body Weight; Carcinogens; Diabetes Complications; Disease Models, Animal; Gastric Mucosa; Insulin; Leptin; Male; Methylnitrosourea; Mice; Mice, Inbred Strains; Precancerous Conditions; Stomach Neoplasms

Breast cancer continues to be a major cause of cancer deaths in women. Estrogen, which is also produced by the adipose tissue, is held responsible for the elevated risk of breast cancer in obese women. However, the adipose tissue secrets hormones and adipokines such as leptin and IGF-I and these substances could also contribute to an increased breast cancer risk for obese women. In this study, the impact of obesity on cell proliferation was investigated. The carcinogen 7, 12, dimethylbenz[a]anthracene (DMBA) was administered to normal weight and diet-induced obese female Sprague-Dawley rats. Cell proliferation was evaluated by immunohistological staining of BrdU-incorporation. In the mammary glands and inguinal lymphatic nodes of the obese rats, cell proliferation was significantly increased, indicating a significant influence of obesity on breast cancer. Effects of leptin, estrogen, and IGF-I on the proliferation of MCF-7 cells in vitro were assessed using an MTT assay. Cell culture experiments demonstrated a mitogenic role of these three mediators on cell proliferation. Our data demonstrate a stimulative effect of substances produced by the adipose tissue on breast cancer. Body weight specific cell proliferation suggests that obesity-related adipokines and mediators enhance cell proliferation and increase the risk for breast cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Analysis of Variance; Animals; Body Weight; Breast Neoplasms; Carcinogens; Cell Line, Tumor; Cell Proliferation; Dietary Fats; Disease Models, Animal; Estradiol; Female; Groin; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Leptin; Lymph Nodes; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors

Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin-induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous-endometrial epithelial cells (EEC) (An3Ca, SK-UT2 and Ishikawa), leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1beta); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1beta was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen-activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin-induced cell signaling pathways in endometrial cancer cells.

Topics: Adenocarcinoma; Blotting, Western; Endometrial Neoplasms; Endometrium; Female; Humans; Interleukin-1beta; Leptin; Leukemia Inhibitory Factor; Neovascularization, Pathologic; Protein Kinases; Receptors, Interleukin-1; Receptors, OSM-LIF; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Obesity increases the risk of developing oesophageal adenocarcinoma (OAC) as well as several other cancers. Leptin is secreted by adipocytes and serum leptin levels rise with body mass index. Leptin stimulates proliferation and inhibits apoptosis in OAC cells but the mechanisms are not fully elucidated, Transactivation of the epidermal growth factor receptor (EGFR) is an important signalling mechanism for G-protein-coupled receptors, but the relationship with leptin-type receptors has not been examined and the authors hypothesise that leptin-induced proliferation involves EGFR signalling. This study examines the effect of leptin on EGFR signalling in cultured cell lines. Leptin stimulated proliferation in four OAC lines expressing leptin receptors (OE33, OE19, BIC-1 and FLO) and this was abolished by specific EGFR inhibitors (PD153035 and AG1478). Leptin-induced proliferation was inhibited by neutralising antibodies to transforming growth factor-alpha (TGFalpha and HB-EGF) but not by anti-amphiregulin. Leptin significantly increased gene expression of HB-EGF and TGFalpha as measured by a quantitative real-time polymerase chain reaction (PCR) method but did not alter amphiregulin and EGFR gene expression. Leptin increased extracellular release of HB-EGF and TGFalpha and this was blocked by matrix metalloproteinase (MMP) inhibitors. The MMP inhibitors also abolished leptin-induced proliferation as well as leptin-induced EGFR tyrosine phosphorylation, but did not affect proliferation or EGFR activation induced by TGFalpha. The authors conclude that leptin stimulates OAC proliferation via increased gene expression of HB-EGF and TGFalpha, MMP-mediated extracellular release of HB-EGF and TGFalpha and subsequent activation of EGFR.

Topics: Adenocarcinoma; Amphiregulin; Autoantibodies; Cell Line, Tumor; Cell Proliferation; EGF Family of Proteins; ErbB Receptors; Esophageal Neoplasms; Glycoproteins; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Matrix Metalloproteinases; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation; Transforming Growth Factor alpha; Tyrphostins

To investigate the regulation of leptin expression in human lung adenocarcinoma cells by hypoxia inducible factor-1 (HIF-1alpha) and the mechanism thereof.. Lung adenocarcinoma tissues were collected from 42 patients during operation and samples of corresponding adjacent lung tissue were obtained from 16 of the 42 specimens. The expression levels of HIF-1alpha and leptin were detected by immunohistochemical staining. Human lung adenocarcinoma cells of the line A549 cells were cultured for 0, 12, 24, and 48 h respectively, exposed to hypoxia induced by CoCl2. Other A549 cells were treated with GL331, a kind of HIF-1alpha inhibitor, of the concentrations of 0, 5, 10, or 20 micromol/L under normoxic condition for 24 h, and then were exposed to hypoxia induced by CoCl2 for 24 h. RT-PCR and Western-blotting were used to examine the mRNA and protein expression levels of HIF-1alpha and leptin in different groups.. Immunohistochemistry showed that the positive rates of HIF-1alpha and leptin in the lung adenocarcinoma tissue were 57.1% and 69.0% respectively, both significantly higher than those in the adjacent normal lung tissues (18.8% and 25.0% respectively, both P<0.01). The protein expression levels of HIF-1alpha in the hypoxia 0, 12, 24, and 48 h groups were 0.314+/-0.030, 0.552+/-0.027, 0.743+/-0.015, and 0.799+/-0.010 respectively, and the protein expression levels of leptin were 0.398+/-0.016, 0.633+/-0.036, 0.796+/-0.008, and 0.942+/-0.088 respectively, increasing in a time dependent manner too. The mRNA expression levels of leptin in the 4 hypoxia groups were 0.144+/-0.009, 0.336+/-0.017, 0.524+/-0.013, and 0.671+/-0.021 respectively, increasing in a time dependent manner, however, there was no significant differences in the mRNA expression levels of HIF-1alpha among the groups exposed to hypoxia for different courses of time (all P>0.05). The protein expression levels of HIF-1alpha and leptin, and the mRNA expression levels of leptin in the groups exposed to hypoxia for different courses of time were all significantly higher than those of the control (0 h hypoxia) group (all P<0.01). The mRNA and protein expression levels of leptin in the A549 cells exposed to GL331 and hypoxia were decreased dose-dependently.. The expression of leptin is up-regulated by hypoxia and regulated by HIF-1alpha.

Topics: Adenocarcinoma; Aged; Cell Hypoxia; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging

Obesity increases the risk of developing several cancers including oesophageal adenocarcinoma (OAC). Obesity is characterised by hyperleptinaemia and hypoadiponectinaemia: we have hypothesised that these hormonal factors may contribute to the progression of OAC. We have examined the effects of leptin and adiponectin on proliferation of OAC cells. Leptin-stimulated proliferation in four different OAC lines (OE33, OE19, BIC-1 and FLO) and this was inhibited by globular but not full length adiponectin. All four OAC lines expressed both adiponectin-receptor isoforms (AdipoR1 and AdipoR2). Globular adiponectin also inhibited leptin-induced proliferation in rat IEC-18 cells which only expressed AdipoR1. Specific inhibitors of 5'-AMP-activated protein kinase (Compound C) and serine/threonine phosphatases (okadaic acid) and a specific siRNA to AdipoR1 blocked the anti-proliferative effects of adiponectin. Adiponectin inhibited leptin-induced Akt phosphorylation; this action was sensitive to okadaic acid but not to Compound C. Adiponectin deficiency may contribute to the promotion of OAC in obesity.

Topics: Adenocarcinoma; Adiponectin; AMP-Activated Protein Kinases; Animals; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Enzyme Inhibitors; Esophageal Neoplasms; Humans; Leptin; Multienzyme Complexes; Obesity; Okadaic Acid; Protein Isoforms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rats; Receptors, Adiponectin; RNA Interference

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

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

Obesity and gastro-oesophageal reflux are the main predisposing factors for oesophageal adenocarcinoma. We have examined the effects of transient acid exposure and leptin on OE33 oesophageal adenocarcinoma cells. Leptin and acid individually stimulated proliferation and inhibited apoptosis and the combination was synergistic. Leptin receptor protein levels were unchanged by acid exposure. The COX-2 inhibitor NS 398 blocked the effects of acid and leptin but while both acid and leptin individually significantly increased PGE2 production and COX-2 mRNA levels, the combination was not more effective than either stimulant alone. Leptin synergistically enhanced acid-stimulated EGFR and ERK phosphorylation but did not further increase JNK or p38 MAP kinase phosphorylation. Specific EGFR and ERK inhibitors reduced the effects of leptin and acid alone and in combination. The combination of increased circulating leptin levels in obesity and transient reflux of gastric acid may promote oesophageal carcinogenesis by increasing proliferation and inhibiting apoptosis.

Topics: Acids; Adenocarcinoma; Apoptosis; Cell Proliferation; Cyclooxygenase 2; Enzyme Activation; Epidermal Growth Factor; ErbB Receptors; Esophageal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Humans; Leptin; Receptors, Cell Surface; Receptors, Leptin; Tumor Cells, Cultured

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

Leptin is an adipocyte-derived hormone that regulates body fat stores and feeding behavior. The presence of leptin in stomach epithelium was recently demonstrated in the rat and humans, and gastric leptin has been linked to the control of meal size, local inflammatory responses, and paracrine and autocrine functions through leptin receptors in the stomach. We compared the expression patterns of leptin and of the long variant of the leptin receptor (Ob-Rb) between areas with non-ulcerated mucosa and with hyperplastic polyps, adenoma, or adenocarcinoma to evaluate the expression relative to different disease states. Leptin and Ob-Rb were expressed in hyperplastic polyps, adenoma, and adenocarcinoma. In the gastric adenocarcinoma, leptin was expressed significantly less in the poorly differentiated and diffuse-type groups than in the well-differentiated and moderately differentiated groups or in the intestinal type. Based upon our findings, we suggest the possibility that leptin expression can have a pathophysiologic role about the differentiation or growth pattern of gastric adenocarcinoma. A further series of experiments is necessary to elucidate the pathophysiological role of leptin in the differentiation of gastric adenocarcinoma.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Gastric Mucosa; Humans; Leptin; Middle Aged; Stomach; Stomach Neoplasms

Obesity is an important risk factor for esophageal adenocarcinoma (EAC), and elevated serum leptin is characteristic of obesity. We hypothesized that leptin may have biological effects in promoting esophageal adenocarcinoma and examined the effects of leptin on the OE33 Barrett's-derived EAC line. Proliferation was assessed by dimethylthiazoldiphenyltetra-zoliumbromide and 5-bromo-2'-deoxyuridine incorporation assays and apoptosis by ELISA of intracellular nucleosomes. Intracellular signaling was examined using specific pharmacological inhibitors and direct detection of phosphorylated active kinases. Expression of the long and short leptin receptors by OE33 cells was confirmed by RT-PCR, Western blotting and immunocytochemistry. Leptin stimulated OE33 cell proliferation in a dose-dependent manner and inhibited apoptosis. These effects were dependent on cyclooxygenase (COX)-2 and replicated by adding prostaglandin E2 (PGE2). The effects of PGE2 and leptin were abolished by the EP-4 antagonist AH23848. ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and Janus tyrosine kinase (JAK)-2 were activated upstream of COX-2 induction, whereas the epidermal growth factor receptor and c-Jun NH2-terminal kinase (JNK) were downstream of COX-2. The activation of ERK and Akt but not p38 MAPK was JAK2 dependent. PGE2 stimulated phosphorylation of JNK in an EGF receptor-dependent manner, and activation of the epidermal growth factor receptor required protein kinase C, src, and matrix metalloproteinase activities. We conclude that leptin stimulates cell proliferation and inhibits apoptosis in OAC cells via ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and JAK2-dependent activation of COX-2 and PGE2 production. Subsequent PGE2-mediated transactivation of the epidermal growth factor receptor and JNK activation are essential to the leptin effects. These effects may contribute to the greatly increased risk of esophageal adenocarcinoma in obesity.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Division; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Enzyme Activation; ErbB Receptors; Esophageal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Humans; Janus Kinase 2; JNK Mitogen-Activated Protein Kinases; Leptin; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptors, Cell Surface; Receptors, Leptin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Recombinant Proteins; RNA, Messenger; Transcriptional Activation

To examine the expression of leptin and its receptor, OB-R, in normal gastric mucosa and neoplasia.. By immunohistochemical staining using specific antibodies, we evaluated the expression of leptin and OB-R in 207 gastric carcinomas (100 early and 107 advanced carcinomas) and analyzed their relationship with clinicopathological features.. Both normal gastric epithelium and carcinoma cells expressed a significant level of leptin. In cases with OB-R staining, carcinoma cells showed OB-R-positive expression, but the intensity was weaker than that in normal mucosa. The expression of OB-R showed a significant correlation with the level of leptin expression. The expression levels of both leptin and OB-R tended to increase as the depth of tumor invasion or TMN stage increased (P < 0.01). Lymph node metastasis was detected in 49.5% (47/95) of leptin-strong cases and in 50.5% (48/95) of OB-R-positive cases, and the rate was 33% (37/112) in leptin-weak cases and 17% (19/112) in OB-R-negative cases. Both venous and lymphatic invasion also tended to be observed frequently in positive tumors as compared with negative tumors. Interestingly, in the 96 leptin- or OB-R-positive tumors, hematogenous metastasis was detected preoperatively in 3 (3.1%) patients. In contrast, none of the carcinomas that lacked expression of leptin and OB-R showed hematogenous metastasis.. Overexpression of leptin and expression of OB-R may play a positive role in the process of progression in gastric cancer. Functional upregulation of leptin/OB-R may have a positive role in the development and initial phase of progression in gastric cancer.

Topics: Adenocarcinoma; Aged; Carcinoma, Signet Ring Cell; Disease Progression; Female; Gastric Mucosa; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Male; Middle Aged; Receptors, Cell Surface; Receptors, Leptin; Stomach Neoplasms

Extensive loss of adipose tissue is a hallmark of cancer cachexia but the cellular and molecular basis remains unclear. This study has examined morphologic and molecular characteristics of white adipose tissue in mice bearing a cachexia-inducing tumour, MAC16. Adipose tissue from tumour-bearing mice contained shrunken adipocytes that were heterogeneous in size. Increased fibrosis was evident by strong collagen-fibril staining in the tissue matrix. Ultrastructure of 'slimmed' adipocytes revealed severe delipidation and modifications in cell membrane conformation. There were major reductions in mRNA levels of adipogenic transcription factors including CCAAT/enhancer binding protein alpha (C/EBPalpha), CCAAT/enhancer binding protein beta, peroxisome proliferator-activated receptor gamma, and sterol regulatory element binding protein-1c (SREBP-1c) in adipose tissue, which was accompanied by reduced protein content of C/EBPalpha and SREBP-1. mRNA levels of SREBP-1c targets, fatty acid synthase, acetyl CoA carboxylase, stearoyl CoA desaturase 1 and glycerol-3-phosphate acyl transferase, also fell as did glucose transporter-4 and leptin. In contrast, mRNA levels of peroxisome proliferators-activated receptor gamma coactivator-1alpha and uncoupling protein-2 were increased in white fat of tumour-bearing mice. These results suggest that the tumour-induced impairment in the formation and lipid storing capacity of adipose tissue occurs in mice with cancer cachexia.

Topics: Adenocarcinoma; Adipose Tissue; Animals; Atrophy; Blotting, Western; Body Weight; Cachexia; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; Female; Gene Expression; Glucose Transporter Type 4; Ion Channels; Leptin; Male; Mice; Mice, Inbred Strains; Microscopy, Electron; Mitochondrial Proteins; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Uncoupling Protein 2

To investigate the expression of leptin and leptin receptor (ob-R) in intestinal-type gastric cancer and precancerous lesions, and to explore the possible mechanism and role of the leptin system in developing intestinal-type gastric adenocarcinoma.. Immunohistochemistry was performed to examine the expression of leptin and leptin receptor in archival samples of gastric adenocarcinoma and preneoplastic lesions, including intestinal metaplasia and mild to severe gastric epithelial dysplasia. Positive staining was identified and percentage of positive staining was graded.. Dual expression of leptin and leptin receptor were detected in 80% (16/20) intestinal metaplasia, 86.3% (25/30) mild gastric epithelial dysplasia, 86.7% (26/30) moderate gastric epithelial dysplasia, 93.3% (28/30) severe gastric epithelial dysplasia, 91.3% (55/60) intestinal-type gastric adenocarcinoma and 30.0% (9/30) diffuse-type gastric carcinoma. The percentage of dual expression of leptin and leptin receptor in intestinal-type gastric adenocarcinoma was significantly higher than that in diffuse-type gastric adenocarcinoma (c2 = 37.022, P<0.01).. Our results indicate the presence of an autocrine loop of leptin system in the development of intestinal-type gastric adenocarcinoma.

Topics: Adenocarcinoma; Humans; Immunohistochemistry; Leptin; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Precancerous Conditions; Receptors, Cell Surface; Receptors, Leptin; Stomach Neoplasms

Eighty-five to 95% of esophageal cancer patients suffer dysphagia. Yet, few studies have focused on this symptom, and four 'myths' persist: (i) dysphagia cannot be measured; (ii) chemotherapy cannot palliate it; (iii) dysphagia predicts a poor prognosis; (iv) dysphagia is associated with a frustratingly insatiable appetite. Forty-four patients with metastatic esophageal cancer participated in this quality of life/translational component of a previously reported clinical trial. All were monitored for chemotherapy efficacy and toxicity and completed questionnaires on dysphagia and appetite at baseline and every 6 weeks. The appetite hormones, leptin and neuropeptide y, were also assessed. Forty-five per cent of patients could easily swallow solid foods; all others had varying dysphagia, thus enabling exploration of these four 'myths.' First, a single-item visual analog scale (Swallowing Scale), demonstrated excellent agreement with a previously validated questionnaire (81% at baseline), thus reminding us that dysphagia is measurable. Second, chemotherapy was associated with a trend towards improved dysphagia (P = 0.059). Third, dysphagia did not predict tumor response or survival. Fourth, dysphagia was not associated with appetite, leptin or neuropeptide y. This study helps to dispel these four 'myths' and underscores the need for further quality of life research on dysphagia.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Analysis of Variance; Appetite; Cohort Studies; Deglutition Disorders; Esophageal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Prognosis; Quality of Life; Surveys and Questionnaires; Treatment Outcome

In the Western world, the incidence of oesophageal adenocarcinoma has increased over the last 30 years coinciding with a decrease in the prevalence of Helicobacter pylori. Trends of increasing oesophageal adenocarcinoma can be linked causally to increasing gastro-oesophageal reflux disease (GORD) which can be linked to an increasingly obese population. However, there is no plausible biological mechanism of association between H. pylori, obesity, and GORD. Ghrelin, a peptide produced in the stomach, which regulates appetite, food intake, and body composition, was studied in H. pylori positive asymptomatic subjects.. Plasma ghrelin, leptin, and gastrin were measured for six hours after an overnight fast, before and after cure of H. pylori in 10 subjects. Twenty four hour intragastric acidity was also assessed.. After cure, median (95% confidence intervals) integrated plasma ghrelin increased from 1160.5 (765.5-1451) pg/ml x h to 1910.4 (1675.6-2395.6) pg/ml x h (p=0.002, Wilcoxon's rank sum test), a 75% increase. This was associated with a 14% increase in 24 hour intragastric acidity (p=0.006) and non-significant changes in leptin and gastrin. There was a significant positive correlation between plasma ghrelin and intragastric acidity (r(s) 0.44, p=0.05, Spearman's rank correlation).. After H. pylori cure, plasma ghrelin increased profoundly in asymptomatic subjects. This could lead to increased appetite and weight gain, and contribute to the increasing obesity seen in Western populations where H. pylori prevalence is low. This plausible biological mechanism links H pylori, through increasing obesity and GORD, to the increase in oesophageal adenocarcinoma observed in the West.

Topics: Adenocarcinoma; Adult; Esophageal Neoplasms; Female; Gastric Acidity Determination; Gastrins; Gastroesophageal Reflux; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Peptide Hormones; Radioimmunoassay

Leptin is a hormone primarily produced by adipocytes and serum leptin is elevated in obese persons. One risk factor associated with adenocarcinoma of the esophagus is obesity. We hypothesized that leptin would have stimulatory effects on esophageal adenocarcinoma and alter apoptosis in vitro.. Barrett's esophageal adenocarcinoma cells (BIC-1 and SEG-1) were cultured with human recombinant leptin (80 ng/mL) for 24 hours. Cell growth was determined by MTT assay. Apoptosis and necrosis was measured after 16 hours of treatment with leptin using a Cell Death Kit.. Exogenous leptin stimulated cell proliferation in both cell lines. No changes in apoptosis or necrosis resulted between control and leptin-treated groups.. We have shown that leptin increases the proliferation of human esophageal adenocarcinoma, but does not alter cell apoptosis or necrosis. The data suggest that leptin stimulates esophageal adenocarcinoma growth by nonapoptotic mechanisms. Leptin antagonism may have potential efficacy in esophageal cancer therapy.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Division; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Humans; Leptin; Necrosis; Recombinant Proteins; Stimulation, Chemical; Tumor Cells, Cultured

With a rapid-emergence, chemically induced animal model for breast cancer, an experiment designed to test the hypothesis that energy restriction (ER) induces the loss of carcinogen-initiated cells from the mammary gland, thereby conferring a permanent protective effect against the development of cancer, failed to support this hypothesis. Nonetheless, this experiment served to define an experimental approach and a time frame on which to focus mechanistic inquiry. With an ER and energy repletion (ER-REP) protocol as a tool for identifying potential mediators of the cancer-inhibitory activity of ER, concomitant changes in plasma corticosterone and insulin-like growth factor 1 during energy restriction and repletion were observed. The relationship of the timing of these hormonal changes to the time frame of change in the carcinogenic response during ER-REP was consistent with the role of both hormones in mediating the protective effects of ER. However, a similar pattern of change in the energy-regulated hormone leptin indicated that its role in cancer inhibition also merits consideration.

Topics: Adenocarcinoma; Animals; Caloric Restriction; Corticosterone; Diet; Energy Metabolism; Female; Insulin-Like Growth Factor I; Leptin; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylnitrosourea; Rats; Rats, Sprague-Dawley; Receptors, Estrogen

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

In order to investigate the effect of serum leptin and its potential as a parameter for the accessment of nutritional status of patients with cancer, serum leptin concentration, body mass index (BMI), blood erythrocyte, hemoglobin, serum albumin, lipid and lipoprotein concentration of 325 cancer patients and 66 healthy controls are meatured. The incidence of patients with BMI < 18.5, hypoalbumia, anemia, hypercholesterolemia, and hypertriglyceridemia is 23%, 14%, 42%, 17.2%, and 21.4% respectively. The incidence of patients with BMI < 18.5 in pulmonary carcinoma is obviously lower than that of those with gastric carcinoma (P = 0.022). The incidence of patients with hyperglycosemia and hypertriglyceridemia in pulmonary carcinoma is obviously higher than that of those with gastric carcinoma (P = 0.003 and P = 0.029 respectively). Serum leptin concentration in the patients with malnutrition is significantly lower than that of those with no malnutrition and that of those obese patients (P = 0.000). There is no significant difference in serum leptin concentration between patients with cancer and healthy control persons with same gender and with BMI value ranged from 18.5 to 25. It is shown that the BMI, gender and serum albumin concentration are all influencing factors to the serum leptin concentration and the serum leptin concentration is significantly correlated with BMI, gender and serum albumin concentrations (r = 0.599-0.698, P = 0.000). The above mentioned results from this study indicate that there is a high anemia incidence of patients with cancer. Serum leptin concentration can reflect the changes in BMI and nutritional status of the patients with cancer. The serum leptin concentration has the potential of being a parameter for assessing nutritional status of the patients with cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Female; Humans; Leptin; Lung Neoplasms; Male; Middle Aged; Nutritional Status; Stomach Neoplasms

The abnormalities of lipid metabolism observed in cancer cachexia may be induced by a lipid-mobilizing factor produced by adenocarcinomas. The specific molecules and metabolic pathways that mediate the actions of lipid-mobilizing factor are not known. The mitochondrial uncoupling proteins-1, -2 and -3 are suggested to play essential roles in energy dissipation and disposal of excess lipid. Here, we studied the effects of lipid-mobilizing factor on the expression of uncoupling proteins-1, -2 and -3 in normal mice. Lipid-mobilizing factor isolated from the urine of cancer patients was injected intravenously into mice over a 52-h period, while vehicle was similarly given to controls. Lipid-mobilizing factor caused significant reductions in body weight (-10%, P=0.03) and fat mass (-20%, P<0.01) accompanied by a marked decrease in plasma leptin (-59%, P<0.01) and heavy lipid deposition in the liver. In brown adipose tissue, uncoupling protein-1 mRNA levels were elevated in lipid-mobilizing factor-treated mice (+96%, P<0.01), as were uncoupling proteins-2 and -3 (+57% and +37%, both P<0.05). Lipid-mobilizing factor increased uncoupling protein-2 mRNA in both skeletal muscle (+146%, P<0.05) and liver (+142%, P=0.03). The protein levels of uncoupling protein-1 in brown adipose tissue and uncoupling protein-2 in liver were also increased with lipid-mobilizing factor administration (+49% and +67%, both P=0.02). Upregulation by lipid-mobilizing factor of uncoupling proteins-1, -2 and -3 in brown adipose tissue, and of uncoupling protein-2 in skeletal muscle and liver, suggests that these uncoupling proteins may serve to utilize excess lipid mobilized during fat catabolism in cancer cachexia.

Topics: Adenocarcinoma; Adipose Tissue, Brown; Animals; Blotting, Northern; Blotting, Western; Body Weight; Carrier Proteins; DNA Primers; Humans; Ion Channels; Leptin; Lipid Metabolism; Liver; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Peptides; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3; Up-Regulation

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

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

Obesity increases the risk of colon cancer, whereas physical activity reduces the risk. Plasma levels of leptin increase in proportion to the level of obesity and are reduced by physical activity. Leptin acts as a growth factor for several cell types and thus may provide a biological explanation for the observed epidemiological risk factors. The aim of this study was to investigate whether leptin is a growth factor for colonic epithelial cells.. The presence of the leptin receptor in human colon cancer cell lines was assessed using reverse-transcription polymerase chain reaction and immunoblotting, and its presence in human colonic tissue was assessed by immunohistochemistry. The effects of leptin in vitro on HT29 cells were assessed by assessing p42/44 mitogen-activated protein kinase phosphorylation, thymidine incorporation, and cell numbers and in vivo in C57BL/6 mice by colonic bromodeoxyuridine incorporation.. The leptin receptor is expressed in human colon cancer cell lines and human colonic tissue. Stimulation with leptin leads to phosphorylation of p42/44 mitogen-activated protein kinase and increases proliferation in vitro and in vivo.. Leptin is a growth factor in colonic epithelial cells and one that may provide a biological explanation for the observed associations between obesity, physical activity, and colon cancer.

Topics: Adenocarcinoma; Animals; Bromodeoxyuridine; Carrier Proteins; Colonic Neoplasms; Epithelium; Female; Growth Substances; Humans; Leptin; Mice; Obesity; Protein Kinases; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Thymidine; Tumor Cells, Cultured

Weight loss normally stimulates hunger, through mechanisms that include falls in circulating leptin and insulin, leading to stimulation of hypothalamic neuropeptide Y (NPY). Here, we investigated the leptin, insulin and NPY to clarify why hunger is suppressed in mice with severe cachexia due to the MAC16 adenocarcinoma. MAC16-bearing mice progressively lost weight (19% below controls) and fat (- 61%) over 16 days after tumour transplantation, while total food intake fell by 10%. Pair-fed mice showed less wasting, with final weight being 9% and fat mass 25% below controls. Plasma leptin fell by 85% in MAC16 and 51% in pair-fed mice, in proportion to loss of fat. Plasma insulin was also reduced by 49% in MAC16 and 53% in pair-fed groups. Hypothalamic leptin receptor (OB-Rb) mRNA was significantly increased in both MAC16 (+ 223%) and pair-fed (+192%) mice. Hypothalamic NPY mRNA was also significantly raised in MAC16 (+152%) and pair-fed (+ 99%) groups, showing negative correlations with plasma leptin and insulin, and a positive association with OB-Rb mRNA. In MAC16-induced cachexia, leptin production and hypothalamic OB-Rb and NPY expression are regulated appropriately in response to fat depletion. Therefore, suppression of hunger is probably due to tumour products that inhibit NPY transport or release, or that interfere with neuronal targets downstream of NPY.

Topics: Adenocarcinoma; Adipose Tissue; Animals; Blotting, Northern; Cachexia; Carrier Proteins; Eating; Female; Gene Expression Regulation; Hunger; Hypothalamus; Insulin; Leptin; Mice; Neoplasm Transplantation; Neuropeptide Y; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

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

Weight loss in cancer cachexia is attributable to decreased food intake and/or enhanced energy expenditure. We investigated the roles of the uncoupling proteins (UCPs) UCPI, -2, and -3 in a murine model of cachexia, the MAC16 adenocarcinoma. Weight fell to 24% below that of non-tumor-bearing controls (P < 0.01) 18 days after MAC16 inoculation, with significant reductions in fat-pad mass (-67%; P < 0.01) and muscle mass (-20%; P < 0.01). Food intake was 26-60% lower (P < 0.01) than in controls on days 17-18. Non-tumor-bearing mice, pair-fed to match MAC16-induced hypophagia, showed less weight loss (10% below controls, P < 0.01; 16% above MAC-16, P < 0.01) and smaller decreases in fat-pad mass (21% below controls, P < 0.01). Core temperature in MAC16 mice was significantly lower (-2.4 degrees C, P < 0.01) than in controls, and pair-feeding had no effect. MAC16 mice showed significantly higher UCP1 mRNA levels in brown adipose tissue (BAT) than in controls (+63%, P < 0.01), and pair-feeding had no effect. UCP2 and -3 expression in BAT did not differ significantly between groups. By contrast, UCP2 mRNA levels in skeletal muscle were comparably increased in both MAC16 and pair-fed groups (respectively, 183 and 163% above controls; both, P < 0.05), with no significant difference between these two groups. Similarly, UCP3 mRNA was significantly higher than controls in both MAC16 (+163%, P < 0.05) and pair-fed (+253%, P < 0.01) groups, with no significant difference between the two experimental groups. Overexpression of UCP1 in BAT in MAC16-bearing mice may be an adaptive response to hypothermia, which is apparently induced by tumor products; increased thermogenesis in BAT could increase total energy expenditure and, thus, contribute to tissue wasting. Increased UCP2 and -3 expression in muscle are both attributable to reduced food intake and may be involved in lipid utilization during lipolysis in MAC16-induced cachexia.

Topics: Adenocarcinoma; Adipose Tissue, Brown; Analysis of Variance; Animals; Blotting, Northern; Body Temperature; Body Weight; Cachexia; Carrier Proteins; Eating; Female; Gene Expression; Ion Channels; Leptin; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Neoplasms, Experimental; Protein Biosynthesis; Proteins; RNA, Messenger; RNA, Ribosomal, 18S; Time Factors; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3

Several lines of evidence from in vivo animal experiments and human studies suggest that leptin, a peptide secreted from adipose tissue, plays a role in regulating food intake and energy expenditure. However, the signal transduction mechanism of leptin in its target cells remains unknown thus far since leptin-responsive cell lines have not been available yet. We found that leptin caused the tyrosine phosphorylation of several proteins in human renal cell carcinoma cells, ACHN cells, in which STAT-1, but neither STAT-3 nor STAT-5, was involved. An ACHN cell line would serve as a useful tool for analyzing the signal transduction mechanism of leptin.

Topics: Adenocarcinoma; Blotting, Western; DNA-Binding Proteins; Humans; Kidney Neoplasms; Leptin; Obesity; Phosphorylation; Proteins; Recombinant Proteins; STAT1 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Tyrosine