leptin and Colonic-Polyps

Epidemiological studies over the last few decades have shown a strong influence of obesity on colon cancer risk and its progression. These studies have primarily focussed on the role of adipokines in driving cancer progression. We investigated the incidence of cancerous polyp formation and tumor progression in presence and absence of functional leptin along with exploring the role of tumor necrosis factor α (TNFα), under obese condition. By utilizing diet induced obese and genetically obese mice, carcinogen induced colon polyp formation was investigated. Experiments were performed using tumor tissues and cell lines to delineate the inter-relationship between leptin and TNFα. Data shown in this report indicates that in leptin knockdown obese mice, AOM/DSS induced polyps are smaller and lesser in numbers as compared to AOM/DSS induced polyps in diet induced obese mice. Further in vitro experiments suggest that abrogation of leptin associated pathways promote TNFα induced apoptosis. Mechanistically, we report that TNFα induces p53 independent cell death through up regulation of p53 upregulated modulator of apoptosis (PUMA). TNFα induced PUMA was inhibited upon pre- exposure of cells to leptin, prior to TNFα treatment. Collectively these results indicate that obesity due to leptin non-functionality facilitates TNFα induced colon cancer cell death.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Azoxymethane; Colonic Neoplasms; Colonic Polyps; Dextran Sulfate; Diet, High-Fat; Gene Knockdown Techniques; HCT116 Cells; Humans; Incidence; Leptin; Mice; Mice, Knockout; Mice, Obese; Neoplasms, Experimental; Obesity; Recombinant Proteins; Signal Transduction; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins; Up-Regulation

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

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

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 increases the risk of colorectal cancer and adenomatous polyp, and one of the underlying mechanisms of this increase is considered to be due to the growth promoting effects of adipokines, such as leptin. In order to investigate this finding, leptin expression in the colonic tissue and blood leptin concentration of the colonic adenoma patients were compared to those of the control group.. Colonic adenoma tissues were obtained by polypectomy (n=60). In these patients, normal colonic mucosa at remote areas from the polyp was also obtained and blood samples were collected as well. Age and sex matched control subjects were selected among those who showed normal colonic mucosa in health screening colonoscopy (n=60).. There was no significant difference in serum leptin concentration between the colonic adenoma patients and control subjects. Leptin expression was noted in 43.3% of the colonic adenomas, but only in 6.7% of normal colonic mucosa from the control subjects (p<0.01). There were ten cases of concurrent adenocarcinoma in situ in adenoma patients, eight cases of which expressed leptin (p=0.01). In adenoma group, leptin expression rate was significantly high in larger adenomas and in obese patients (p<0.05). However, there was no statistically significant relationship between leptin expression in colonic mucosa and serum leptin level.. Leptin expression was more frequently observed in colonic adenomas, especially in larger adenomas associated with adenocarcinoma in situ, but blood leptin level was not related to tissue leptin expression. Leptin expression was more frequently observed in obese patients from the adenoma group. Therefore, leptin may play an important role in colonic tumorigenesis and progression, especially in obese patient.

Topics: Adenoma; Adult; Aged; Body Mass Index; Colonic Neoplasms; Colonic Polyps; Female; Humans; Intestinal Mucosa; Leptin; Male; Middle Aged; Obesity; Odds Ratio; Waist Circumference

The role of altered levels of insulin, leptin and adiponectin in contributing to the observed increased risk of colon cancer associated with obesity remains to be determined. Elevated insulin and leptin associated with obesity are linked to inflammatory responses. Conversely, adiponectin levels are reduced in obese individuals and this hormone is generally associated with anti-inflammatory responses. Inflammatory cytokines are key components of processes linked with carcinogenesis. Insulin, leptin and adiponectin receptor expression profiles were assessed in human normal, adenomatous polyp and tumour tissue. Insulin, leptin and adiponectin regulation of inflammatory cytokines previously identified as being associated with early events in colon carcinogenesis were further investigated here using a surrogate colon epithelial cell line and a custom designed GeXP assay of the inflammatory cytokines (CCL20, CXCL1, CXCL2, CXCL3, CXCL11, IL1RN, CXCL4, IL8, CCL19, CCL21, CCL23, CCL5, IL10RB and TNFRSF1A). Mean insulin, leptin and adiponectin receptor expression levels were lower in adenomatous polyp samples in comparison with normal and tumour tissue. In contrast to leptin, insulin significantly reduced CCL20 and CXCL11 and increased CXCL3 expression. Full length adiponectin, but not globular adiponectin, induced CCL5, CXCL1, CXCL3 and CCL20 gene expression. GeXP assay permitted measurement of changes in gene expression of cytokines in response to insulin and adiponectin, indicating the potential for insulin and adiponectin regulation of mediators of inflammation associated with early events in colon carcinogenesis.

Topics: Adiponectin; Aged; Aged, 80 and over; Cell Line, Tumor; Colon; Colonic Neoplasms; Colonic Polyps; Cytokines; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation Mediators; Insulin; Leptin; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Real-Time Polymerase Chain Reaction; Receptors, Adiponectin