Insulin, leptin, and tumoral adipocytes promote murine pancreatic cancer growth.
ABSTRACT Obesity accelerates development and growth of human pancreatic cancer. We recently reported similar findings in a novel murine model of pancreatic cancer in congenitally obese mice. The current experiments were designed to evaluate the effects of diet-induced obesity on pancreatic cancer growth.
Thirty C57BL/6J female mice were fed either control 10% fat (n = 10) or 60% fat diet (n = 20) starting at age 6 weeks. At 11 weeks, 2.5 × 10(5) PAN02 murine pancreatic cancer cells were inoculated. After 6 weeks, tumors were harvested. Serum adiponectin, leptin, insulin, and glucose concentrations were measured. Tumor proliferation, apoptosis, adipocyte content, and tumor-infiltrating lymphocytes were evaluated.
The diet-induced obesity diet led to significant weight gain (control 21.3 ± 0.6 g; diet-induced obesity 23.1 ± 0.5 g; p = 0.03). Mice heavier than 23.1 g were considered "Overweight." Tumors grew significantly larger in overweight (1.3 ± 0.3 g) compared to lean (0.5 ± 0.2 g; p = 0.03) mice; tumor size correlated positively with body weight (R = 0.56; p < 0.02). Serum leptin (3.1 ± 0.7 vs. 1.4 ± 0.2 ng/ml) and insulin (0.5 ± 0.2 vs. 0.18 ± 0.02 ng/ml) were significantly greater in overweight mice. Tumor proliferation, apoptosis, and tumor adipocyte volume were similar. T and B lymphocytes were observed infiltrating tumors from lean and overweight mice in similar number.
These data show that diet-induced obesity accelerates the growth of murine pancreatic cancer.
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ABSTRACT: The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiological studies have highlighted associations between increased serum leptin levels and increased tumor growth, while adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify areas of intervention and facilitate advancement in the field.Clinical Cancer Research 01/2013; · 7.84 Impact Factor
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ABSTRACT: Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival. We analyzed survival by prediagnostic BMI assessed in 1986 among 902 patients from two large prospective cohorts diagnosed from 1988 to 2010. We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and stage. We evaluated the temporal association of BMI with survival by grouping reported BMI by 2-year lag-time intervals before diagnosis. The multivariable-adjusted HR for death was 1.53 (95% CI, 1.11 to 2.09) comparing patients with BMI ≥ 35 kg/m(2) with those with BMI < 25 kg/m(2) (P trend = .001), which was similar after adjustment for stage. The association of BMI with survival was stronger with longer lag times between reported BMI and cancer diagnosis. Among patients with BMI collected 18 to 20 years before diagnosis, HR for death was 2.31 (95% CI, 1.48 to 3.61; P trend < .001), comparing obese with healthy-weight patients. No statistically significant differences were seen by cohort, smoking status, or stage, although the association was stronger among never-smokers (HR, 1.61; 95% CI, 1.01 to 2.57; P trend = .002) than ever-smokers (HR, 1.36; 95% CI, 0.86 to 2.15; P trend = .63), comparing BMI ≥ 35 kg/m(2) with BMI < 25 kg/m(2). Higher prediagnostic BMI was associated with more advanced stage at diagnosis, with 72.5% of obese patients presenting with metastatic disease versus 59.4% of healthy-weight patients (P = .02). Higher prediagnostic BMI was associated with statistically significantly decreased survival among patients with pancreatic cancer from two large prospective cohorts.Journal of Clinical Oncology 10/2013; · 18.04 Impact Factor
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ABSTRACT: BACKGROUND: Obesity has been consistently associated with increased risk of pancreatic cancer incidence and mortality. However, studies of obesity and overall survival in patients with pancreatic cancer are notably lacking, especially in population-based studies. METHODS: Active and passive follow-up were used to determine vital status and survival for 510 pancreatic cancer patients diagnosed from 1995 to 1999 in a large population-based case-control study in the San Francisco Bay Area. Survival rates were computed using Kaplan-Meier methods. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated in multivariable Cox proportional hazards models as measures of the association between pre-diagnostic obesity and pancreatic cancer survival. RESULTS: An elevated hazard ratio of 1.3 (95 % CI, 0.91-1.81) was observed for obese [body mass index (BMI) ≥ 30] compared with normal range BMI (<25) patients. Associations between BMI and overall survival did not statistically significantly vary by known prognostic and risk factors (all p-interaction ≥0.18), yet elevated HRs consistently were observed for obese compared with normal BMI patients [localized disease at diagnosis (HR, 3.1), surgical resection (HR, 1.6), ever smokers (HR, 1.6), diabetics (HR, 3.3)]. Poor survival was observed among men, older patients, more recent and current smokers, whereas improved survival was observed for Asian/Pacific Islanders. CONCLUSIONS: Our results in general provide limited support for an association between pre-diagnostic obesity and decreased survival in patients with pancreatic cancer. Patterns of reduced survival associated with obesity in some patient subgroups could be due to chance and require assessment in larger pooled studies.Cancer Causes and Control 09/2012; · 3.20 Impact Factor