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: Pancreatic cancer (PC) is one of the most lethal malignant diseases with the worst prognosis. It is ranked as the fourth leading cause of cancer-related deaths in the United States. Many risk factors have been associated with PC. Interestingly, large numbers of epidemiological studies suggest that obesity and diabetes, especially type-2 diabetes, are positively associated with increased risk of PC. Similarly, these chronic diseases (obesity, diabetes, and cancer) are also a major public health concern. In the U.S. population, 50 percent are overweight, 30 percent are medically obese, and 10 percent have diabetes mellitus (DM). Therefore, obesity and DM have been considered as potential risk factors for cancers; however, the focus of this article is restricted to PC. Although the mechanisms responsible for the development of these chronic diseases leading to the development of PC are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin resistance could be useful strategy for the prevention and/or treatment of PC. A large number of studies have demonstrated that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of PC. In this review article, we will discuss the potential roles of metformin and TZD anti-diabetic drugs as anti-tumor agents in the context of PC and will further discuss the complexities and the possible roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes, and PC.Biochimica et Biophysica Acta 12/2010; 1815(2):135-46. DOI:10.1016/j.bbcan.2010.11.003 · 4.66 Impact Factor
- Gastroenterology 01/2011; 140(5). DOI:10.1016/S0016-5085(11)62327-5 · 13.93 Impact Factor
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ABSTRACT: Obesity affects more than one third of the U.S. population and is associated with increased risk and/or disease severity for several chronic diseases, including cancer. In contrast, calorie restriction (CR) consistently inhibits cancer across species and cancer types. Differential effects on globally active circulatory proteins, particularly insulin-like growth factor-1 (IGF-1), provide a plausible mechanistic explanation for the energy balance-cancer link. Diet-induced changes in circulating IGF-1 modulate IGF-1R/EGFR activation and downstream signaling to Akt and mTOR. These dietary energy balance effects on signaling ultimately modulate the levels and/or activity of cell cycle regulatory proteins, regulating proliferation, and modulating susceptibility to tumor development. Selective targeting of mTORC1 potently inhibits tumorigenesis in several model systems producing CR mimetic effects. Targeting this and other pathways modulated by dietary energy balance may lead to the development of strategies for cancer chemoprevention and for reversing the effects of obesity on cancer development and progression.Annals of the New York Academy of Sciences 07/2011; 1229(1):7-17. DOI:10.1111/j.1749-6632.2011.06099.x · 4.31 Impact Factor