leptin and Colonic-Neoplasms

Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer.

Topics: Adipose Tissue; Animals; Colon; Colonic Neoplasms; Humans; Inflammation Mediators; Intestinal Mucosa; Leptin; Obesity; Receptors, Leptin

Obesity is currently reaching epidemic levels worldwide and is a major predisposing factor for a variety of life-threatening diseases including diabetes, hypertension and cardiovascular diseases. Recently, it has also been suggested to be linked with cancer. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5-2 fold with obesity-associated colon cancer accounting for 14-35% of total incidence. Several factors, altered in obesity, may be important in cancer development including increased levels of blood insulin, insulin-like growth factor I, leptin, TNF-alpha, IL-6 as well as decreased adiponectin. A unifying characteristic of all these factors is that they increase the activity of the PI3K/Akt signal pathway. The PI3K/Akt signal pathway in turn activates signals for cell survival, cell growth and cell cycle leading to carcinogenesis. Here we review the evidence that PI3K/Akt and its downstream targets are important in obesity-associated colon cancer and thus, that targeted inhibition of this pathway could be employed for the prevention of obesity-associated colon cancer and incorporated into the therapy regime for those with irremovable colon cancers.

Topics: Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Colonic Neoplasms; Comorbidity; Enzyme Inhibitors; Humans; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Obesity; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha

Obesity is a risk factor for many diseases. Thirty per cent of Americans are viewed as super obese; therefore, we need to find a solution. We already know about the diseases associated with obesity such as high blood pressure, diabetes, sleep apnoea, etc. Lately, there has been an increased interest in understanding if cancer is related to obesity. In this paper, we review the incidence of colon cancer and obesity. Insulin is the best established biochemical mediator between obesity and colon cancer. Hyperinsulinaemia, such as occurs in type II diabetes, is important in the pathogenesis of colon cancer. All adipose tissue is not equal. Visceral abdominal fat has been identified as the essential fat depot for pathogenetic theories that relate obesity and colon cancer. The genders differ as regards to how the relationship between obesity and colon cancer has been evaluated. Obesity imposes a greater risk of colon cancer for men of all ages and for premenopausal women than it does for postmenopausal women. Regular exercise reduces the risk of developing colon cancer and the risk of death from colon cancer should it develop. We believe that a combination of waist circumference (WC) and body mass index (BMI) measurements is recommended to assess the obesity related risk of developing colon cancer. Radiographic assessments of visceral abdominal fat may eventually prove to be the best means of assessing a patient's obesity related risk of developing colon cancer. Although WC is better established as a measure of obesity than BMI, the evidence for colon cancer risk is not secure on this point; combining BMI and WC measurements would appear, at present, to be the wisest approach for colon cancer risk assessment. Doctors who wish to decrease their patients' risk of dying of colon cancer should advise weight loss and exercise. Conversely, physicians and public health authorities should consider both exercise and obesity when designing colon cancer screening protocols. Morphometric cut offs should be adjusted, if possible, for age, sex, ethnicity, and height.

Topics: Adipose Tissue; Colonic Neoplasms; Exercise; Female; Humans; Insulin; Leptin; Male; Menopause; Obesity; Risk Factors; Sex Factors

Employing targeting ligands on the surface of liposomes has the great potential to improve therapeutic efficacy and decreases off-target effects of liposomal formulations. In the present study, a leptin-derived peptide (Lp31) was evaluated to optimize the therapeutic efficacy of PEGylated liposomal Doxorubicin (PLD, Caelyx®). Leptin is an appetite regulatory hormone that is secreted into the blood circulation by the adipose tissue and it functions via its over expressed receptors (Ob-R) in a wide variety of cancers. Lp31, as targeting ligand, was conjugated to Maleimide-PEG2000-DSPE and then post-inserted into Caelyx. The anti-tumor activity and therapeutic efficacy of leptin modified Caelyx were evaluated and compared with Caelyx. The in vitro experiments demonstrated enhanced cytotoxicity and cellular uptake of Lp31-targeted Caelyx in C26 cell line compared to Caelyx. In BALB/c mice bearing C-26 murine carcinoma, Lp31 modified Caelyx groups exhibited significantly higher doxorubicin concentration at tumor tissue. Furthermore, Lp31 modified Caelyx at the dose of 10 mg/kg resulted in significant tumor growth inhibition and enhanced survival time compared to Caelyx. According to these results, the novel Lp31-liposomal doxorubicin offers great promise for the treatment of colon cancer and merits further investigation.

Topics: Animals; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Doxorubicin; Leptin; Liposomes; Mice; Mice, Inbred BALB C; Peptides; Polyethylene Glycols; Tissue Distribution

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

Topics: Animals; Cell Movement; Colonic Neoplasms; Gene Expression; HCT116 Cells; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; NF-E2-Related Factor 2; Obesity; Sirtuin 1; Xenograft Model Antitumor Assays

Obesity, an immense epidemic affecting approximately half a billion adults, has doubled in prevalence in the last several decades. Epidemiological data support that obesity, due to intake of a high-fat, western diet, increases the risk of colon cancer; however, the mechanisms underlying this risk remain unclear. Here, utilizing next generation RNA sequencing, we aimed to determine the high-fat diet (HFD) mediated expression profile in mouse colon and the azoxymethane/dextran sulfate sodium model of colon cancer. Mice on HFD had significantly higher colonic inflammation, tumor burden, and a number of differentially expressed transcripts compared to mice on regular diet (RD). We identified 721 transcripts differentially expressed in mouse HFD colon that were in a shared pattern with colonic tumors (RD and HFD). Importantly, in mouse colon, HFD stimulated an expression signature strikingly similar to human colon cancer, especially those with inflammatory microsatellite instability. Furthermore, pathway analysis of these transcripts demonstrated their association with active inflammation and colon cancer signaling, with leptin and Wnt as the top two transcripts elevated in mouse HFD colon shared with tumors. Moreover, in mouse colon, HFD-stimulated tumorigenic Wnt pathway activation was further validated by upregulation of β-catenin transcriptional targets. Finally, in human colon cancer, upregulation of leptin pathway members was shown with a large network of dysregulated transcripts being linked with worse overall survival.

Topics: Animals; beta Catenin; Colon; Colonic Neoplasms; Diet, High-Fat; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; HT29 Cells; Humans; Inflammation; Inflammation Mediators; Leptin; Mice; Mice, Inbred C57BL; Obesity; Signal Transduction; Wnt Signaling Pathway

Ellagic acid (EA) has been proposed as a promising candidate for therapeutic use in colon cancer. Investigation of the effectiveness of EA in a leptin-enriched model might have been given a little interest. Here in, we investigated the anti-tumor effect of EA in the presence of leptin to reflect on therapeutic use of EA in obesity-linked colon cancer. Proven effective in leptin-enriched microenvironment, EA inhibited cell proliferation of HCT-116 and CaCo-2 cell lines, modulated cell cycle, translocated Bax to the mitochondrial fraction of cells, activated caspase-8, and reduced PCNA expression. The current study findings cast a beam of light on the potential therapeutic use of EA in obesity-related colon carcinogenesis.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers; Caco-2 Cells; Caspase 8; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Ellagic Acid; Humans; Leptin; Proliferating Cell Nuclear Antigen; Signal Transduction; Tumor Microenvironment

Obesity is a risk factor for colorectal cancer (CRC). Normal and tumor cells respond to metabolic hormones, such as leptin and insulin. Thus, obesity-associated resistance to these hormones likely leads to changes in gene expression and behavior of tumor cells. However, the mechanisms affected by leptin and insulin signaling in CRC cells remain mostly unknown.. We hypothesized that microRNAs (miRNAs) are involved in the regulation of tumorigenesis-related gene expression in CRC cells by leptin and insulin. To test this hypothesis, miRNA levels in the CRC-derived cell lines HCT-116, HT-29 and DLD-1 were profiled, following leptin and insulin treatment. Candidate miRNAs were validated by RT-qPCR. Predicted miRNA targets with known roles in cancer, were validated by immunoblots and reporter assays in HCT-116 cells. Transfection of HCT-116 cells with candidate miRNA mimic was used to test in vitro effects on proliferation and invasion.. Of ~800 miRNAs profiled, miR-4443 was consistently up-regulated by leptin and insulin in HCT-116 and HT-29, but not in DLD-1, which lacked normal leptin receptor expression. Dose response experiments showed that leptin at 100 ng/ml consistently up-regulated miR-4443 in HCT-116 cells, concomitantly with a significant decrease in cell invasion ability. Transfection with miR-4443 mimic decreased invasion and proliferation of HCT-116 cells. Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay. The up-regulation of miR-4443 by leptin or insulin was attenuated by the inhibition of MEK1/2.. Our findings suggest that miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway and increase the risk of metastatic CRC.

Topics: 3' Untranslated Regions; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Insulin; Leptin; MAP Kinase Signaling System; MicroRNAs; Models, Biological; Nuclear Receptor Coactivator 1; RNA Interference; TNF Receptor-Associated Factor 4; Up-Regulation

Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet-induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth. We hypothesize that mice rendered insulin resistant due to consumption of a high-fat Western diet will show increased and accelerated tumor growth. Homozygous Rag1

Topics: Adipose Tissue, White; Animals; Chemokine CCL2; Colonic Neoplasms; Diet, High-Fat; Diet, Western; Dietary Fats; Disease Models, Animal; Epididymis; Heterografts; Humans; Inflammation; Insulin; Insulin Resistance; Intra-Abdominal Fat; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mice, Inbred Strains; Obesity; Phosphorylation; Receptor Protein-Tyrosine Kinases; Signal Transduction

The aim of the study was to investigate the serum adipokine levels and expression of adipokine receptors (AdipoR1, AdipoR2) in patients with endometrial and colon cancer in relation with the main clinical morphological parameters (tumor invasion, lymph node involvement). The study included 60 endometrial cancer patients with I-II Stage and 31 patients with colon cancer (T2-4N0-2M0). Serum adipokine levels, the level of soluble form of the leptin receptor (sOb-R) and AdipoR1 and AdipoR2 expression were evaluated with ELISA. In endometrial cancer serum leptin and adiponectin levels were associated not only with metabolic disorders but also with cervical invasion. In colon cancer serum leptin level was associated with lymph node involvement. The data obtained showed the potential implication of serum adipokines into tumor invasion and metastasis. In both sites intratumoral levels of AdipoR1 H AdipoR2 were not associated with the presence of metabolic syndrome. The AdipoR1 level was related with myometrial invasion. In colon cancer patients, AdipoR1 and AdipoR2 expressions were associated with lymph node involvement, and AdipoR1 expression was correlated with tumor size. The obtained results demonstrated involvement of adipose tissue hormones (leptin and adiponectin) and adiponectin receptors (AdipoR1 and AdipoR2) in tumor growth, invasion and lymphogenic metastasis.

Topics: Adipokines; Adiponectin; Adult; Aged; Cervix Uteri; Colonic Neoplasms; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Receptors, Adiponectin

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

This study determined the efficacy of carnosic acid (CA) for suppressing colon carcinogenesis associated with excess adiposity.. Cell growth regulation by CA was evaluated in HT-29 colon adenocarcinoma cells cocultured with 3T3-L1 adipocytes. To determine the in vivo efficacies, male A/J mice were divided into four groups and fed one of the following experimental diets for 11 wk: 15% fat, 45% fat, 45% fat + 0.01% CA, or 45% fat + 0.02% CA. Azoxymethane was administered at the beginning of experimental diet and two cycles of dextran sodium sulfate were supplied 1 wk after the azoxymethane injection. The proliferation of HT-29 cells cocultured with 3T3-L1 cells was significantly higher than proliferation of control cells (p < 0.05). CA treatment suppressed the growth of cocultured HT-29 cells through cell cycle arrest and enhanced apoptosis by inhibiting leptin receptor (Ob-R) signaling, including Akt and extracellular signal-regulated kinase (ERK) phosphorylation. CA supplementation in vivo decreased the number of colon tumors and reduced circulating concentrations of leptin, adiponectin, insulin, and insulin-like growth factor 1. Colonic expression of Ob-R, insulin receptor (IR), p-Akt, p-ERK, B-cell lymphoma extra large (Bcl-xL), and cyclinD1 protein was also suppressed in animals fed CA.. CA appears to alleviate adipocity-related acceleration of colon tumor formation.

Topics: 3T3-L1 Cells; Abietanes; Adipocytes; Adipogenesis; Adiponectin; Adiposity; Animals; Apoptosis; Azoxymethane; bcl-X Protein; Cell Proliferation; Colon; Colonic Neoplasms; Cyclin D1; Dextran Sulfate; Extracellular Signal-Regulated MAP Kinases; HT29 Cells; Humans; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Mice; Plant Extracts; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Receptors, Leptin; STAT3 Transcription Factor

Obesity is a key risk factor for the development of colon cancer; however, the endocrine/paracrine/metabolic networks mediating this connection are poorly understood. Here we hypothesize that obesity results in secreted products from adipose tissue that induce malignancy-related metabolic alterations in colon cancer cells. Human HCT116 colon cancer cells, were exposed to conditioned media from cultured human adipose tissue fragments of obese vs. non-obese subjects. Oxygen consumption rate (OCR, mostly mitochondrial respiration) and extracellular acidification rate (ECAR, mostly lactate production via glycolysis) were examined vis-à-vis cell viability and expression of related genes and proteins. Our results show that conditioned media from obese (vs. non-obese) subjects decreased basal (40%, p<0.05) and maximal (50%, p<0.05) OCR and gene expression of mitochondrial proteins and Bax without affecting cell viability or expression of glycolytic enzymes. Similar changes could be recapitulated by incubating cells with leptin, whereas, leptin-receptor specific antagonist inhibited the reduced OCR induced by conditioned media from obese subjects. We conclude that secreted products from the adipose tissue of obese subjects inhibit mitochondrial respiration and function in HCT116 colon cancer cells, an effect that is at least partly mediated by leptin. These results highlight a putative novel mechanism for obesity-associated risk of gastrointestinal malignancies, and suggest potential new therapeutic avenues.

Topics: Adipose Tissue; Adult; Blotting, Western; Cell Respiration; Cell Survival; Colonic Neoplasms; Culture Media, Conditioned; Glycolysis; Humans; Leptin; Middle Aged; Mitochondria; Mitochondrial Proteins; Obesity; Oxygen Consumption; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured

Obesity-related metabolic abnormalities include a state of chronic inflammation and adipocytokine imbalance, which increase the risk of colon cancer. Curcumin, a component of turmeric, exerts both cancer preventive and antiinflammatory properties. Curcumin is also expected to have the ability to reverse obesity-related metabolic derangements. The present study examined the effects of curcumin on the development of azoxymethane (AOM)-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Feeding with a diet containing 0.2% and 2.0% curcumin caused a significant reduction in the total number of colonic premalignant lesions compared with basal diet-fed mice. The expression levels of tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2 (COX-2) mRNAs on the colonic mucosa of AOM-treated mice were significantly decreased by curcumin administration. Dietary feeding with curcumin markedly activated AMP-activated kinase, decreased the expression of COX-2 protein, and inhibited nuclear factor-κB activity on the colonic mucosa of AOM-treated mice. Curcumin also increased the serum levels of adiponectin while conversely decreasing the serum levels of leptin and the weights of fat. In conclusion, curcumin inhibits the development of colonic premalignant lesions in an obesity-related colorectal carcinogenesis model, at least in part, by attenuating chronic inflammation and improving adipocytokine imbalance. Curcumin may be useful in the chemoprevention of colorectal carcinogenesis in obese individuals.

Topics: Adiponectin; Adipose Tissue; AMP-Activated Protein Kinase Kinases; Animals; Anticarcinogenic Agents; Azoxymethane; Colon; Colonic Neoplasms; Curcumin; Cyclooxygenase 2; Dietary Supplements; Interleukin-6; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NF-kappa B; Obesity; Organ Size; Precancerous Conditions; Protein Kinases; Tumor Necrosis Factor-alpha

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

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

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

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

Clinical studies indicate that high blood levels of leptin or matrix metalloproteinase-7 (MMP-7; matrilysin) proteins are associated with tumor progression of human colorectal cancer (CRC). Leptin could play an important role in cell migration and invasion of cancer cells. Our previous study indicated that lycopene could inhibit the proliferation of human colon cancer cells in vitro. However, the inhibitory effects of lycopene on the progression of human colon cancer cells have not been demonstrated yet. In this study, we investigated the inhibitory effects of lycopene on tumor progression including cell invasion and MMP-7 expression in leptin-stimulated human colon cancer cells in vitro. Our results demonstrated that lycopene significantly inhibited leptin-mediated cell invasion and MMP-7 expression in human colon cancer HT-29 cells. Lycopene could augment the expression and stability of E-cadherin proteins. Our results showed that MAPK/ERK and PI3K/Akt signaling pathways played important roles in leptin-mediated MMP-7 expression and cell invasion. Lycopene could effectively inhibit the phosphorylation of Akt, glycogen synthase kinase-3β (GSK-3β) and ERK 1/2 proteins. The molecular mechanisms of lycopene were in part through decreases in nuclear levels of AP-1 and β-catenin proteins. These novel findings suggested that lycopene could act as a chemopreventive agent to suppress MMP-7 expression and leptin-mediated cell invasion in human colon cancer HT-29 cells.

Topics: Anticarcinogenic Agents; Carotenoids; Colonic Neoplasms; Gene Expression; HT29 Cells; Humans; Leptin; Lycopene; Matrix Metalloproteinase 7; Neoplasm Invasiveness

Obesity is known to be a risk factor for colon carcinogenesis. Although there are several reports on the chemopreventive abilities of dietary flavonoids in chemically induced colon carcinogenesis, those have not been addressed in an obesity-associated carcinogenesis model. In the present study, the effects of 3 flavonoids (chrysin, quercetin and nobiletin) on modulation of the occurrence of putative preneoplastic lesions, aberrant crypt foci (ACF), and beta-catenin-accumulated crypts (BCACs) in the development of colon cancer were determined in male db/db mice with obesity and diabetic phenotypes. Male db/db mice were given 3 weekly intraperitoneal injections of azoxymethane (AOM) to induce the ACF and BCAC. Each flavonoid (100ppm), given in the diet throughout the experimental period, significantly reduced the numbers of ACF by 68-91% and BCAC by 64-71%, as well as proliferation activity in the lesions. Clinical chemistry results revealed that the serum levels of leptin and insulin in mice treated with AOM were greater than those in the untreated group. Interestingly, the most pronounced suppression of development of preneoplastic lesions and their proliferation were observed in the quercetin-fed group, in which the serum leptin level was lowered. Furthermore, quercetin-feeding decreased leptin mRNA expression and secretion in differentiated 3T3-L1 mouse adipocytes. These results suggest that the present dietary flavonoids are able to suppress the early phase of colon carcinogenesis in obese mice, partly through inhibition of proliferation activity caused by serum growth factors. Furthermore, they indicate that certain flavonoids may be useful for prevention of colon carcinogenesis in obese humans.

Topics: Animals; Antioxidants; Azoxymethane; Carcinogens; Colonic Neoplasms; Dietary Supplements; Flavones; Flavonoids; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Precancerous Conditions; Quercetin

Leptin, a pleiotropic hormone regulating food intake and metabolism, plays an important role in the regulation of inflammation and immunity. We previously demonstrated that serum leptin levels are profoundly increased in mice which received azoxymethane (AOM) and dextran sulfate sodium (DSS) as tumor-initiator and -promoter, respectively, in a colon carcinogenesis model. In this study, we attempted to address underlying mechanism whereby leptin is up-regulated in this rodent model. Five-week-old male ICR mice were given a single intraperitoneal injection of AOM (week 0), followed by 1% DSS in drinking water for 7 days. Thereafter, the weights of visceral fats and the serum concentration of leptin were determined at week 20. Of interest, the relative epididymal fat pad and mesenteric fat weights, together with serum leptin levels in the AOM and/or DSS-treated mice were markedly increased compared to that in untreated mice. In addition, leptin protein production in epididymal fat pad with AOM/DSS-treated mice was 4.7-fold higher than that of control. Further, insulin signaling molecules, such as protein kinase B (Akt), S6, mitogen-activate protein kinase/extracellular signaling-regulated kinase 1/2, and extracellular signaling-regulated kinase 1/2, were concomitantly activated in epididymal fat of AOM/DSS-treated mice. This treatment also increased the serum insulin and IGF-1 levels. Taken together, our results suggest that higher levels of serum insulin and IGF-1 promote the insulin signaling in epididymal fat and thereby increasing serum leptin, which may play an crucial role in, not only obesity-related, but also -independent colon carcinogenesis.

Topics: Animals; Azoxymethane; Carcinogens; Colitis; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Insulin; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred ICR; Signal Transduction

Active migration of tumor cells is a prerequisite for the development of metastasis and tumor progression, and is regulated by a variety of extracellular ligands. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5- to 2-fold with obesity-associated colon cancer accounting for 14-35% of total incidence. In obese individuals, serum levels of leptin are markedly increased, and therefore, we have investigated the impact of this adipocytokine on the migration of various human colon carcinoma cell lines such as SW480, SW620, and HCT116. Leptin significantly enhanced the migratory activity of all three cell lines, and the strongest effect was observed in SW480 cells, which increased their locomotor activity from 28% spontaneously locomoting cells to 50%. The intracellular signal transduction regulating this pro-migratory effect involves the activation of the transcription factor signal transducer and activator of transcription-3 via Janus kinases, but also the activity of src tyrosine kinases, focal adhesion kinase, exclusively protein kinase Cdelta, and the phosphatidyl-inositol-3-kinase, as proven by the use of particular inhibitors and target-specific small interfering RNAs. Herein, we deliver new evidence for a modulatory role of leptin in the regulation of colon cancer progression by stimulating tumor cell migration. Thus, our findings have potential clinical implications, because understanding the impact of leptin on tumor cell migration and the underlying signal transduction mechanisms is mandatory for future development of novel therapeutics to treat obesity-associated colorectal cancer.

Topics: Carcinoma; Cell Movement; Colonic Neoplasms; Disease Progression; HCT116 Cells; Humans; Janus Kinases; Leptin; Phosphatidylinositol 3-Kinases; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Transcription Factors; Tumor Cells, Cultured

Obesity results in increased circulating levels of specific adipokines, which are associated with colon cancer risk. The disease state is associated with increased leptin, insulin, IGF-1, and IL-6. Conversely, adiponectin levels are decreased in obese individuals. Previously, we demonstrated adipokine-enhanced cell proliferation in preneoplastic, but not normal, colon epithelial cells, demonstrating a differential effect of adipokines on colon cancer progression in vitro. Using a model of late stage carcinoma cancer cell, namely murine MC-38 colon carcinoma cells, we compared the effect of obesity-associated adipokines (leptin, insulin, IGF-1, and IL-6) on MC-38 cell proliferation and determined whether adiponectin (full length or globular) could modulate adipokine-induced cell proliferation. We show that insulin and IL-6, but not leptin and IGF-1, induce proliferation in MC-38 cells. Adiponectin treatment of MC-38 cells did not inhibit insulin-induced cell proliferation but did inhibit IL-6-induced cell proliferation by decreasing STAT-3 phosphorylation and activation. Nitric oxide (NO) production was increased in MC-38 cells treated with IL-6; co-treatment with adiponectin blocked IL-6-induced iNOS and subsequent NO production. These data are compared to previously reported findings from our laboratory using the YAMC (model normal colon epithelial cells) and IMCE (model preneoplastic) cells. The cell lines are utilized to construct a model summarizing the hormonal consequences of obesity and the impact on the differential regulation of colon epithelial cells along the continuum to carcinoma. These data, taken together, highlight mechanisms involved in obesity-associated cancers and may lead to potential-targeted therapies.

Topics: Adipokines; Adiponectin; Animals; Carcinoma; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Female; Humans; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Obesity; STAT3 Transcription Factor

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

Topics: Adipocytes; Animals; Brain-Derived Neurotrophic Factor; Colonic Neoplasms; Genes, APC; Housing, Animal; Hypothalamus; Immunocompetence; Leptin; Melanoma; Mice; Mice, Inbred C57BL; Neoplastic Processes; Random Allocation; Receptors, Adrenergic, beta; Signal Transduction; Social Environment

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

Adipose tissue secretes factors linked to colon cancer risk including leptin. A hallmark of cancer is sustained angiogenesis. While leptin promotes angiogenesis in adipose tissue, it is unknown whether leptin can induce epithelial cells to produce factors that may drive angiogenesis, vascular development and therefore cancer progression. The purpose of this study was to compare the effects of leptin-stimulated colon epithelial cells differing in adenomatous polyposis coli (Apc) genotype (gatekeeper tumor suppressor gene for colon cancer) on angiogenesis. We employed novel colonic epithelial cell lines derived from the Immorto mouse [young adult mouse colon (YAMC)] and the Immorto-Min mouse [Immorto-Min colonic epithelial cell (IMCE)], which carries the Apc Min mutation, to study the effects of leptin-stimulated colon epithelial cells on angiogenesis. We utilized ex vivo rat mesenteric capillary bioassay and human umbilical vein endothelial cell (HUVEC) models to study angiogenesis. IMCE cells stimulated with leptin produced significantly more vascular endothelial growth factor (VEGF) than YAMC (268 +/- 18 versus 124 +/- 8 pg/ml; P < 0.01) cells. Leptin treatment induced dose-dependent increases in VEGF only in IMCE cells. Conditioned media from leptin (50 ng/ml)-treated IMCE cells induced significant capillary formation compared with control, which was blocked by the addition of a neutralizing antibody against VEGF. Conditioned media from leptin-treated IMCE cells also induced HUVEC cell proliferation, chemotaxis, upregulation of adhesion proteins and cell-signaling activation resulting in nuclear factor kappa B nuclear translocation and DNA binding due to VEGF. This is the first study demonstrating that leptin can induce preneoplastic colon epithelial cells to orchestrate VEGF-driven angiogenesis and vascular development, thus providing a specific mechanism and potential target for obesity-associated cancer.

Topics: Adenomatous Polyposis Coli Protein; Animals; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Chemotaxis; Colonic Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Humans; Leptin; Male; Mesentery; Mice; Neovascularization, Physiologic; NF-kappa B; Obesity; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; Umbilical Veins; Vascular Endothelial Growth Factor A

Topics: Colonic Neoplasms; Extracellular Signal-Regulated MAP Kinases; HT29 Cells; Humans; Leptin; Proto-Oncogene Proteins c-akt; Signal Transduction

Leptin serum levels are about 5 times higher in obese people than in normal individuals. We aimed at investigating the signaling pathways induced by leptin in the human colonic cell lines LS174T and HM7. Both cells expressed the leptin transmembrane Ob-receptor. Leptin activated the mitogen-activated protein kinase pathway, induced invasion of colonic cells and concomitantly increased the formation of lamellipodial structures. A direct and novel dose- and time-dependent activation of RhoA, Cdc42 and Rac1 by leptin is demonstrated in these aggressive colon cancer cells. The activation of the Rho family of GTPases was amenable to specific inhibition: Wortmannin inhibited leptin-induced Rac1 and Cdc42 activation but did not affect RhoA activation, and inhibited the formation of leptin-induced lamellipodia and cell invasion. The Rac1 inhibitor NSC23766 inhibited only leptin-induced Rac1 activation and concomitantly, lamellipodium formation and cell invasion. The Src kinase inhibitor II (SrcKI-II) exerted a positive effect on RhoA activation, inhibited tyrosine phosphorylation of p190RhoGAP and inhibited leptin-induced Cdc42 activation and leptin-induced lamellopodium formation and cell invasion. The specific JAK2 inhibitor AG490 exerted a positive effect on Rac1 and Cdc42 activation by leptin and concomitantly inhibited RhoA activation. AG490 did not inhibit leptin-induced lamellopodium formation or cell invasion. Our findings clearly indicate that leptin activates PI3K and Src kinase pathways in the metastatic colon cancer cells LS174T and HM7. These signaling pathways induce the activation of Rac1 and Cdc42, lamellopodium formation and concomitantly enhanced cell invasion, but leptin activation of RhoA is not associated with enhanced cell locomotion and invasion. Understanding in-depth the pathways involved in leptin-associated enhanced cell locomotion and invasion may contribute with the design of novel therapeutics to treat obesity-associated advanced colorectal cancer.

Topics: cdc42 GTP-Binding Protein; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Enzyme Activation; Humans; Leptin; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; rac1 GTP-Binding Protein; Receptors, Leptin; rho GTP-Binding Proteins; Signal Transduction

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.

Topics: Animals; Anticarcinogenic Agents; Azoxymethane; Carcinoma; Catechin; Cholesterol; Colonic Neoplasms; Diabetes Mellitus, Experimental; Drug Evaluation, Preclinical; Insulin; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred C57BL; Precancerous Conditions; Receptor, IGF Type 1; Triglycerides

Leptin may play an important role in colorectal cancer because of its role in energy balance, insulin and inflammation. We evaluated the LEP rs2167270 (19 G > A) and rs7799039 (-2548 G > A) polymorphisms and the leptin receptor, LEPR rs6588147 (located in intron 2), polymorphism with risk of developing colon cancer in a study of 1,567 cases and 1,965 controls. We evaluated the effects of the polymorphisms with body mass index (BMI), recent use of aspirin/NSAIDs and genetic variations in genes related to insulin signaling pathways including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), and insulin-related substrates 1 and 2 (IRS1, IRS2) and the vitamin D receptor (VDR). We observed a slight reduction in colon cancer risk with the AA LEP rs2167270 genotype (OR 0.79 95% CI 0.64, 0.98) and although not reaching statistical significance, with the combined GG LEP rs2167270 and GG LEPR rs6588147 (OR 0.70, 95% CI 0.49, 1.02) genotypes. BMI did not interact with any of these polymorphisms to alter colon cancer risk. However, recent aspirin/NSAID use significantly interacted with both LEP polymorphisms. Likewise, variants of IGF1 and IRS2 interacted with the LEP rs2167270 polymorphism. VDR polymorphisms interacted with all LEP and LEPR polymorphisms. These data support an association between LEP and colon cancer. They also suggest that the mechanisms linking leptin to colon cancer may be independent of energy balance.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Body Mass Index; Case-Control Studies; Colonic Neoplasms; Female; Genotype; Humans; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Leptin; Life Style; Male; Middle Aged; Phosphoproteins; Polymorphism, Single Nucleotide; Receptors, Leptin

Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.

Topics: Animals; Antioxidants; Azoxymethane; Carcinogens; Cell Division; Cell Line, Tumor; Colitis; Colonic Neoplasms; Flavones; Humans; Leptin; Male; Mice; Mice, Inbred ICR

Our objective was to compare the effects of a low-carbohydrate diet to a high-carbohydrate/calorie-restricted diet on weight loss, hormones, and transplanted colon tumor growth. Eighty male C57BL/6 mice consumed a diet-induced obesity regimen (DIO) ad libitum for 7 weeks. From Weeks 8 to 14, the mice consumed a 1) DIO diet ad libitum (HF); 2) low-carbohydrate diet ad libitum (LC); 3) high-carbohydrate diet ad libitum (HC); or 4) HC calorie restricted diet (HC-CR). MC38 cells were injected at Week 15. At the time of injection, the HC-CR group displayed the lowest body weight (25.5 +/- 0.57 g), serum insulin-like growth factor I (IGF-I; 135 +/- 56.0 ng/ml), and leptin (1.0 +/- 0.3 ng/ml) levels. This group also exhibited the longest time to palpable tumor (20.1 +/- 0.9 days). Compared to the HF group, the HC group exhibited lower body weight (39.4 +/- 1.4 vs. 32.9 +/- 0.7 g, respectively), IGF-I (604 +/- 44.2 vs. 243.4 +/- 88.9 ng/ml, respectively), and leptin (15.6 +/- 2.2 vs. 7.0 +/- 0.7 ng/ml, respectively) levels but similar tumor growth. IGF-I levels were lower in the LC group (320.0 +/- 39.9 ng/ml) than the HF group, but tumor growth did not differ. These data suggest LC diets do not slow colon tumor growth in obese mice.

Topics: Animals; Caloric Restriction; Colonic Neoplasms; Diet, Carbohydrate-Restricted; Energy Intake; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Random Allocation; Weight Loss; Xenograft Model Antitumor Assays

Obesity is a major risk factor for the development of colon cancer. Secretion of the hormone leptin from adipocytes is increased in obesity, and serum levels are proportional to body fat mass. Serum leptin levels are an independent risk factor for colon cancer. Leptin receptors are expressed in normal, premalignant and malignant colonic epithelia. We have investigated the effects of leptin on proliferation and apoptosis of colonic cancer cells and the early signalling events involved.. Proliferation of HT-29 colon cancer cells in response to leptin was assessed by 3-[4, 5-dimethylthiazol-2-y-l]-2, 5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was quantified by enzyme-linked immunosorbent assay (ELISA) for intracellular nucleosomes. Signalling pathways involved were determined by using specific inhibitors, quantification of phosphorylated active intermediates and ELISA of active nuclear-translocated transcription factors.. Leptin stimulated HT-29 cell proliferation and inhibited both serum-starvation and celecoxib-induced apoptosis. The proliferative and anti-apoptotic effects of leptin were abolished by inhibition of JAK2 with AG490, phosphatidylinositol 3'-kinase (PI3 kinase) with LY294002 and c-Jun NH(2)-terminal kinase (JNK) with SP600125. Stimulation of HT-29 cells with leptin increased phosphorylation of JAK2, Akt and JNK. Activation of JAK2 was upstream of PI3 kinase/Akt but not of JNK. Activation of JAK2 was followed by activation and nuclear translocation of STAT3 and JNK activation led to increased activator protein 1 (AP-1) transcriptional activity.. Leptin stimulates proliferation and inhibits apoptosis in human colon cancer cells and may be an important factor in the increased incidence of colon cancer in obesity. This effect involves JAK2, PI3 kinase and JNK and activation of the oncogenic transcription factors signal transducer and activator of transcription (STAT)3 and AP-1.

Topics: Apoptosis; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Enzyme Activation; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinase 2; JNK Mitogen-Activated Protein Kinases; Leptin; Phosphatidylinositol 3-Kinases; Phosphotransferases; Proto-Oncogene Proteins c-akt

The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people.

Topics: Animals; Azoxymethane; Carcinogens; Cholesterol; Colon; Colonic Neoplasms; Diet; Dietary Supplements; Fatty Liver; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred Strains; Plant Extracts; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Triglycerides

Obesity, a risk factor for colon cancer, is associated with elevated serum levels of leptin, a protein produced by adipocytes. The aim of the present study was to clarify the effects of adipose tissue on colon cancer proliferation by using cultured cell lines. To achieve this, colon cancer cells (CACO-2, T84, and HT29) were cocultured with adipose tissue, isolated mature adipocytes, and isolated preadipocytes in a three-dimensional collagen gel culture system. The adipocytes and preadipocytes used were isolated from C57BL/6J and leptin-deficient ob/ob mice. Proliferation of the cancer cells was evaluated by nuclear bromodeoxyuridine uptake. The adipose tissue, mature adipocytes, and preadipocytes isolated from C57BL/6J mice significantly increased the proliferation of the colon cancer cells. This trophic effect of mature adipocytes on the cancer cell lines was observed only for cells from lean littermates and not for those from ob/ob mice. In contrast, the trophic effect of preadipocytes was not abolished in ob/ob mice, and this finding was supported by the result that leptin had a trophic effect on cancer cells. In conclusion, adipocytes were able to enhance the proliferation of colon cancer cells in vitro, partly via leptin, suggesting that adipose tissues, including mature adipocytes and preadipocytes, may promote the growth of colorectal cancer.

Topics: Adipocytes, White; Adipose Tissue; Animals; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Collagen; Colonic Neoplasms; Gels; HT29 Cells; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Receptors, Cell Surface; Receptors, Leptin; Stromal Cells

Obesity is associated with increased levels of leptin. The mitogenic actions of leptin have been identified in various cell types. Because obesity may be a risk factor for colonic cancer, the proliferative and antiapoptotic effects of leptin on colonic cancer cells and the role of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K) signalling were investigated.. Three human colonic cancer cell lines (T(84), HT29/Cl.19A and Caco-2) were treated with leptin. Cell proliferation was measured using the XTT colorimetric assay and apoptosis by a cell death enzyme-linked immunosorbent assay. Inhibitors of MAPK and PI3-K were used to evaluate the role of these signalling pathways. Phosphorylation of the downstream components extracellular signal-regulated kinase (ERK) 1/2 and Akt was detected by western blotting.. Leptin increased cell number in all cell lines in a dose-dependent manner and reduced the number of apoptotic cells in a cell line-dependent manner. Leptin also caused ERK1/2 and Akt phosphorylation. Pretreatment with inhibitors of MAPK and PI3-K inhibited these responses, attenuated the mitogenic action of leptin and abolished its antiapoptotic effects.. Chronic increases in leptin concentration may enhance the growth of colonic cancers via MAPK and PI3-K pathways. These effects of leptin could provide a link between obesity and colonic cancer, and may represent a target for anticancer drug development.

Topics: Analysis of Variance; Apoptosis; Cell Proliferation; Colonic Neoplasms; Enzyme-Linked Immunosorbent Assay; Humans; Immunoblotting; Leptin; Mitogen-Activated Protein Kinases; Obesity; Phosphatidylinositol 3-Kinases; Risk Factors; Tumor Cells, Cultured

Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase, an essential enzyme responsible for S-adenosylmethionine (SAMe) biosynthesis. MAT1A is expressed in liver, whereas MAT2A is widely distributed. In liver, increased MAT2A expression is associated with growth, while SAMe inhibits MAT2A expression and growth. The role of MAT2A in colon cancer in unknown. The aims of this study were to examine whether MAT2A expression and SAMe and its metabolite methylthioadenosine (MTA) can modulate growth of colon cancer cells.. Studies were conducted using resected colon cancer specimens, polyps from Min mice, and human colon cancer cell lines RKO and HT-29. MAT2A expression was measured by real-time polymerase chain reaction and cell growth by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide assay.. In 12 of 13 patients and all 9 polyps from Min mice, the MAT2A messenger RNA levels were 200%-340% of levels in adjacent normal tissues, respectively. Epidermal growth factor, insulin-like growth factor 1, and leptin increased growth and up-regulated MAT2A expression and MAT2A promoter activity in RKO and HT-29 cells. SAMe and MTA lowered the baseline expression of MAT2A and blocked the growth factor-mediated increase in MAT2A expression and growth in colon cancer cell lines. Importantly, the mitogenic effect of these growth factors was inhibited if MAT2A induction was prevented by RNA interference. SAMe and MTA supplementation in drinking water increased intestinal SAMe levels and lowered MAT2A expression.. Similar to the liver, up-regulation of MAT2A also provides a growth advantage and SAMe and MTA can block mitogenic signaling in colon cancer cells.

Topics: Adenosine; Aged; Animals; Cell Death; Cell Division; Colonic Neoplasms; Drug Interactions; Epidermal Growth Factor; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Insulin-Like Growth Factor I; Intestinal Polyps; Leptin; Male; Methionine Adenosyltransferase; Mice; Mice, Inbred C57BL; Middle Aged; Mitogens; Polyamines; Promoter Regions, Genetic; S-Adenosylmethionine

We examined effects of dietary soy protein isolate (SPI) or genistein (GEN; soy isoflavone) during pregnancy on development of colon cancer in male progeny Sprague-Dawley rats. Four groups of rats were used: a lifetime casein-fed group (CAS; control diet), a lifetime SPI-fed group (positive control for protective effect of diet on colon carcinogenesis), a group whose dams received SPI only during pregnancy and CAS thereafter (SPI/CAS), and a group whose dams received CAS+GEN only during pregnancy and CAS thereafter (GEN/CAS). At 47 and 55 days of age, male progeny were administered the intestinal carcinogen azoxymethane (AOM). Tumors, endocrine status, and colon gene expression were evaluated at 20 week post-AOM. The SPI group had 47% decreased colon tumor incidence compared with the CAS group (P<0.05), whereas SPI/CAS, GEN/CAS, and CAS groups did not differ in this regard. Maternal-only SPI increased the percentage of animals bearing multiple colon tumors (P<0.05), an effect not mimicked by GEN. Serum insulin and leptin concentrations were decreased by lifetime SPI (P<0.05), whereas serum IGF-I was elevated in the SPI/CAS group (P<0.05). The SPI/CAS group had reduced serum testosterone levels (P<0.05) and exhibited a tendency for increased mucosal expression of IGF-I receptor and glucose transporter-1 mRNAs. Results indicate an effect of dietary protein type during pregnancy on colon tumor multiplicity and colon tissue gene expression, and serum IGF-I and testosterone in progeny rats as later adults.

Topics: Animals; Animals, Newborn; Azoxymethane; Biomarkers; Caseins; CD3 Complex; Colon; Colonic Neoplasms; Diet; Female; Gene Expression; Genistein; Glucose; Glucose Transporter Type 1; Growth; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Intestinal Mucosa; Leptin; Male; Models, Animal; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1; RNA, Messenger; Soybean Proteins; Testosterone

The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to weight loss, ghrelin and adiponectin levels increase and leptin decreases. Cancer cachexia is a complex metabolic state, characterized by loss of muscle mass and adipose tissue together with anorexia. The authors hypothesized that responses of these hormones may be attenuated in cancer cachexia.. Fasting plasma ghrelin, adiponectin, and leptin levels, as well as weight loss, were determined in 40 cancer patients: 18 of them suffered from cancer-induced cachexia, and 22 served as a comparison group. Hormone levels were measured before administration of cancer therapy.. A similar distribution of age, gender, and diagnosis was observed in both study groups, but the cachectic patients had higher rates of metastatic disease and lower albumin levels. No significant correlation was observed between plasma adiponectin levels and weight loss. Mean plasma ghrelin levels were higher among cachectic compared with noncachectic patients. Notably, the association between ghrelin levels and weight loss was only modest, and in a third of the cachectic patients, ghrelin levels were equal to or lower than those in the noncachectic group. Plasma leptin levels showed gender-dependent associations, and significantly lower levels were found among cachectic women but not among cachectic men.. Results suggested a gender-dependent attenuation of expected physiologic responses to weight loss among cancer cachexia patients. Thus, impaired response of adiponectin, ghrelin, and leptin may play a role in the pathogenesis of cancer cachexia syndrome.

Topics: Adiponectin; Aged; Breast Neoplasms; Cachexia; Colonic Neoplasms; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Peptide Hormones; Sex Factors; Weight Loss

Leptin, the product of the ob gene, has been suggested to increase the risk of colon cancer. However, we have shown that although leptin stimulates epithelial cell proliferation it reduces the development of carcinogen induced preneoplastic lesions in the rat colon. Here, we explored the effect of leptin in vitro on proliferation of human colon cancer cells, and in vivo on the growth of HT-29 xenografts in nude mice and the development of intestinal tumours in Apc(Min/+) mice.. Proliferation of HT-29, LoVo, Caco2, and SW 480 cells was assessed in the absence or presence of leptin (20-500 ng/ml) by 3H-thymidine incorporation and cell count. Leptin (800 microg/kg/day) or its vehicle was delivered for four weeks to nude mice, inoculated with HT-29 cells on day 0, and for six weeks to Apc(Min/+) mice.. Leptin dose dependently stimulated cell DNA synthesis and growth in all cell lines. In nude mice, leptin caused a 4.3-fold increase in plasma leptin levels compared with pair fed controls. This hyperleptinaemia, despite leptin receptor expression in tumours, did not induce significant variation in tumour volume or weight. Tumour Ki-67 index was even inhibited. In leptin treated Apc(Min/+) mice, a 2.4-fold increase in plasma leptin levels did not modify the number, size, or distribution of intestinal adenomas compared with pair fed controls.. Leptin acts as a growth factor on colon cancer cells in vitro but does not promote tumour growth in vivo in the two models tested. These findings do not support a pivotal role for hyperleptinaemia in intestinal carcinogenesis.

Topics: Adenoma; Animals; Apoptosis; Cell Division; Cell Line, Tumor; Colon; Colonic Neoplasms; DNA, Neoplasm; Genes, APC; Humans; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Nude

The authors recently reported that gastrin gene knockout (GAS-KO) mice had an increased risk for colon carcinogenesis in response to azoxymethane (AOM) compared with their wild type (WT) littermates. In the current report, the authors discuss the predisposition of GAS-KO mice to develop obesity and metabolic hormonal changes that may contribute to their increased risk of colon carcinogenesis.. The weight and deposition of fat was monitored in the mice over a 14 month period, using magnetic resonance imaging and nuclear magnetic resonance techniques. Changes in plasma concentrations of ghrelin, leptin, insulin, and glucose were assessed using radioimmunoassay analysis and enzyme-linked immunosorbent assays. Preneoplastic markers of colon carcinogenesis (aberrant crypt foci [ACFs]), in response to AOM, were measured in a subset of obese versus lean GAS-KO mice and were compared with the markers in WT mice.. Increases in visceral adiposity were evident by age 2 months in GAS-KO mice, resulting in macroscopic obesity by age 7 months. Hyperinsulinemia and insulin:glucose ratios were increased significantly in GAS-KO mice as young as 1 month and preceded alterations in nonfasting leptin and ghrelin levels. The number of ACFs per mouse colon were increased significantly in the following order: obese GAS-KO mice > lean GAS-KO mice > WT mice. Fasting plasma insulin levels were 0.88 +/- 0.1 ng/mL, 1.45 +/- 0.3, and 2.76 +/- 0.9 ng/mL in the WT, GAS-KO lean, and GAS-KO obese mice, respectively.. The current results suggest the novel possibility that loss of amidated gastrins may increase adipogenesis, hyperinsulinemia, and colon carcinogenesis in GAS-KO mice. The increase in colon carcinogenesis may be due in part to hyperinsulinemia, increased obesity, and other associated hormone changes that were measured in GAS-KO mice.

Topics: Animals; Azoxymethane; Body Weight; Carcinogens; Colonic Neoplasms; Gastrins; Gene Expression; Ghrelin; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Obesity; Peptide Hormones; Precancerous Conditions; Radioimmunoassay; Thinness

Epidemiological studies have shown that obesity and diabetes mellitus may be risk factors for colon cancer. However, the underlying mechanisms of how these chronic diseases promote colon carcinogenesis remain unknown. C57BL/KsJ-db/db mice have obese and diabetic phenotypes because of disruption of the leptin receptor. The present study was designed to investigate whether development of azoxymethane (AOM)-induced dysplastic and early neoplastic (premalignant) lesions of the colon is modulated in db/db mice. Homozygous db/db mice, heterozygous db/+ mice and littermate controls (+/+) were injected with AOM under food restriction ( approximately 10.8 kcal/mouse/day) and killed 5 weeks after the carcinogen treatment. Their colons were assessed for premalignant lesions induced by AOM. We found a significant increase in the multiplicity of the total premalignant lesions in db/db mice when compared with db/+ or +/+ mice. Phenotypically, serum leptin and insulin levels in db/db mice were significantly higher than those in db/+ or +/+ mice, whereas the body weights and glucose levels in blood of db/db, db/+ and +/+ mice were comparable. In addition, immunostaining of the leptin receptor and insulin-like growth factor-I receptor showed up-regulation of these protein levels specifically in the lesions. Our data indicate that development of AOM-induced premalignant lesions is enhanced in db/db mice with hyperleptinemia and hyperinsulinemia. The results have important implications for further exploration of the possible underlying events that affect the positive association between colon cancer and chronic diseases (obesity and diabetes).

Topics: Animals; Azoxymethane; Blood Glucose; Body Weight; Carcinogens; Colonic Neoplasms; Diabetes Mellitus, Experimental; Heterozygote; Homozygote; Hyperinsulinism; Immunoblotting; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Precancerous Conditions; Receptor, IGF Type 1; Receptors, Cell Surface; Receptors, Leptin

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

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

This study shows that leptin induced a rapid phosphorylation of p42/44 mitogen-activated protein kinase, an enhancement of both NF-kappaB DNA binding and transcriptional activities, and a concentration-dependent increase of HT-29 cell proliferation. These effects are consistent with the presence of leptin receptors on cell membranes. The leptin induction of cell growth was associated with an increase of cell population in S and G2/M phase compared with control cells found in G0/G1 phase of the cell cycle. Moreover, cyclin D1 immunoreactivity was enhanced in leptin-treated HT-29 cells and this increase was essentially associated with cell population in G0/G1 phase. On the other hand, we observed that sodium butyrate inhibited cell proliferation by blocking HT-29 cells in G0/G1 phase of the cell cycle. Interestingly, at physiological concentration, leptin prevented sodium butyrate-induced morphological nucleus changes, DNA laddering and suppressed butyrate-induced cell cycle arrest. This anti-apoptotic effect of leptin was associated with HT-29 cell proliferation and activation NF-kappaB pathways. However, the phosphorylation of p42/44 MAP kinase in response to leptin was reduced in butyrate-treated cells. These data demonstrated that leptin is a potent mitogenic factor for intestinal epithelial cells through the MAP kinase and NF-kappaB pathways. They also showed, for the first time, that leptin promotes colon cancer HT-29 cell survival upon butyrate challenge by counteracting the apoptotic programs initiated by this short chain fatty acid probably through the NF-kappaB pathways. Although further studies are required to unravel the precise mechanism, these data may have significance in the pathogenesis of colorectal cancer and ulcerative colitis diseases.

Topics: Apoptosis; Butyrates; Cell Line, Tumor; Colonic Neoplasms; Drug Antagonism; Humans; Leptin; NF-kappa B; Signal Transduction

Recent studies suggest that leptin, a hormone involved in food intake regulation, released into the circulation and gastrointestinal juice, may be a growth factor for intestine and may be involved in carcinogenesis; however, data are contradictory. This study investigates in rat colonic mucosa (1) the effects of hyperleptinemia on epithelial cell proliferation and development of aberrant crypts, earliest preneoplastic lesions, and (2) whether luminal leptin affects cell proliferation.. Leptin (1 mg/kg/d) or vehicle was administered systemically by miniosmotic pump in Fischer 344 rats either for 7 days (BrdU-labeling indices study) or 23 days (azoxymethane-induced colonic lesions study). The effects of injections or continuous infusion of leptin into the colon were also studied.. In systemic leptin-treated rats, plasma leptin levels were 4- to 5-fold increased (P < 0.008 to P < 0.001); labeling indices were higher in proximal colon than in pair-fed control rats (P = 0.006) but unaffected in distal colon. Unexpectedly, in azoxymethane-treated rats, leptin significantly inhibited aberrant crypt foci formation in the middle and distal colon compared with controls (P = 0.006). Under these conditions, plasma insulin levels were reduced by 41%-58%, but gastrin levels were unchanged. In controls, luminal immunoreactive leptin reached the colon. A 3.6-fold increase in intraluminal leptin had no effect on epithelial cell proliferation.. This study provides the first evidence that leptin reduces the development of chemically induced precancerous lesions in colon, perhaps through decreased insulinemia, and thus does not support an important role for leptin in carcinogenesis promotion. Moreover, the study indicates that leptin is not a potent growth factor for normal intestine.

Topics: Animals; Azoxymethane; Carcinogens; Cell Division; Colonic Neoplasms; Infusion Pumps; Injections; Intestinal Mucosa; Leptin; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Recombinant Proteins

Topics: Animals; Azoxymethane; Carcinogens; Cell Transformation, Neoplastic; Colonic Neoplasms; Intestinal Mucosa; Leptin; Obesity; Precancerous Conditions; Rats; Rats, Zucker

In the intestine, butyrate constitutes the major energy fuel for colonocytes. However, little is known about the transport of butyrate and its regulation in the intestine. In this study we demonstrate that the monocarboxylate transporter (MCT-1) is apically polarized in model human intestinal epithelia and is involved in butyrate uptake by Caco2-BBE cell monolayers. The butyrate uptake by Caco2-BBE cell monolayers displayed conventional Michaelis-Menten kinetics and was found to be pH-dependent, Na(+)-independent, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive, and inhibited by the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxycinnamate and by an excess of unlabeled butyrate. We show that MCT-1 associates with CD147 at the apical plasma membrane in Caco2-BBE cell monolayers. Using antisense CD147, we demonstrate that the association of CD147 with MCT-1 is critical for the butyrate transport activity. Interestingly, we show for the first time hormonal regulation of CD147/MCT-1 mediated butyrate uptake. Specifically, luminal leptin significantly up-regulates MCT-1-mediated butyrate uptake by increasing its maximal velocity (V(max)) without any modification in the apparent Michaelis-Menten constant (K(m)). Finally, we show that luminal leptin up-regulates butyrate uptake in Caco2-BBE monolayers by two distinct actions: (i) increase of the intracellular pool of MCT-1 protein without affecting CD147 expression and (ii) translocation of CD147/MCT-1 to the apical plasma membrane of Caco2-BBE cell monolayers.

Topics: Antigens, CD; Antigens, Neoplasm; Antigens, Surface; Avian Proteins; Basigin; Biological Transport; Blood Proteins; Butyrates; Choline; Colonic Neoplasms; Humans; Intestinal Mucosa; Kinetics; Leptin; Membrane Glycoproteins; Monocarboxylic Acid Transporters; Symporters; Tumor Cells, Cultured

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

We postulated that high fat diet enhances colon cell proliferation and carcinogenesis by elevating serum leptin. To examine this possibility, the present study was conducted to investigate the effect of leptin on the growth of human colon cancer cells (HT29) and the relationship between serum leptin and colon cell proliferation and aberrant crypt foci (ACF) in the 1,2-dimethylhydrazine-treated rats fed graded levels of dietary fat for 28 days. In cell culture experiments, leptin stimulated the growth and proliferation (BrdU incorporation) of colon cancer cells and the expression of c-fos protein. In the in vivo experiments, an elevation of dietary fat caused higher serum leptin and adipose-tissue weight. Colonic cell proliferation (BrdU incorporation), c-fos protein expression and ACF were elevated with increasing dietary fat. There was a significant correlation between serum concentration of leptin and colon cell proliferation and ACF. The results suggest that the enhancement of colon cell proliferation and carcinogenesis by high fat diet is mediated through elevating serum leptin.

Topics: 1,2-Dimethylhydrazine; Adipose Tissue; Animals; Body Weight; Bromodeoxyuridine; Carcinogens; Cell Division; Colonic Neoplasms; Dietary Fats; DNA, Neoplasm; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured

Leptin plays a key role regulating food intake, body weight and fat mass. These critical parameters are associated with an increased risk for digestive and mammary gland cancer in the Western population. Here we determined whether leptin contributes to the invasive phenotype of colonic and kidney epithelial cells at various stages of the neoplastic progression. First, leptin potently (EC50 = 10-30 ng/ml) induces invasion of collagen gels by premalignant familial adenomatous colonic cells PC/AA/C1 and nontumorigenic MDCK kidney epithelial cells, their src-transformed counterparts, and the human adenocarcinoma colonic cells LoVo and HCT-8/S11. Leptin and its Ob-Rb receptors were consistently identified by RT-PCR and immunoblotting in these cell lines, as well as in human colonic epithelial crypts, polyps, colonic tumor resections, and adjacent mucosa. Leptin-induced invasion was effectively blocked by pharmacological inhibitors of several downstream signaling pathways involved in cell transformation, namely, JAK2 tyrosine kinase (AG490), phosphoinositide PI3'-kinase (wortmannin and LY294002), mTOR kinase (rapamycin), and protein kinases C (GF109203X, Gö6976). Accordingly, leptin induces transient elevation of the PI3'-kinase lipid products in JAK2 immunoprecipitates prepared from parental MDCK cells. The leptin effect on invasion was potentiated by the activated form of the small GTPase RhoA and was abrogated by dominant negative mutants of RhoA, Rac1, and the p110alpha of PI3'-K. Our data indicate that leptin may exert a local and beneficial effect on migration of normal colonic epithelial cells and reparation of the inflamed or wounded digestive mucosa. We also emphasize a new role for leptin, linking the nutritional and body fat status to digestive cancer susceptibility by stimulating the invasive capacity of colonic epithelial cells at early stages of neoplasia. This finding has potential clinical implications for colon cancer progression and management of obesity.

Topics: Animals; Carrier Proteins; Cell Line; Cell Movement; Colonic Neoplasms; Dose-Response Relationship, Drug; Enzyme Activation; Enzymes; Gene Expression; Humans; Immunoblotting; Kidney; Leptin; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; rac GTP-Binding Proteins; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; rhoA GTP-Binding Protein; Signal Transduction; Tumor Cells, Cultured