Abstract PL05-01: Mechanistic targets for preventing obesity-related cancers

Abstract

Abstract PL05-01 The prevalence of obesity, an established risk factor for many cancers (1), has risen steadily for the past several decades in the US and many other countries (2). Unfortunately, the mechanisms underlying the obesity and cancer connection are not well understood, and new targets and strategies for offsetting the impact of obesity on cancer risk are urgently needed. Several hormones and growth factors have been implicated as potential mediators of the energy metabolism -carcinogenesis relationship. These include insulin-like growth factor-1 (IGF-1), insulin, several adipokines, and inflammatory/ oxidative stress factors. Calorie restriction (CR), the most commonly recommended dietary strategy for preventing or reversing obesity, has been shown to inhibit spontaneous, transplanted and chemically induced tumors in a variety of animal models (3). In contrast, diet-induced obesity enhances tumorigenesis in many of these same models (3-6). We have also shown in a series of transgenic model systems and microarray studies that the insulin and insulin-like growth factor signaling pathways appear central to many of the anti-cancer effects of CR, as well as the pro-cancer effects of obesity (3). Using AZIP/F1 transgenic mice, which lack white adipose tissue but have high levels of insulin, IGF-1 and inflammatory markers, we have reported that elevated IGF-1 and insulin, as well as increased inflammatory factors (which typically accompany obesity), independent of the adipose tissue per se, appear to be the important dietary targets for disrupting the obesity-cancer link (4). In addition, biochemical and molecular analyses of tissues from lean, overweight and obese mice, as well as IGF-1 deficient mice, established that the Akt and mTOR pathways provide an important target for disrupting the obesity-cancer link via dietary energy balance (5,6). The other side of the energy balance equation is energy expenditure, which includes the energetics of growth, metabolism, thermoregulation and physical activity (the only truly modulatable aspect of energy expenditure). Epidemiologic studies have established that increased physical activity is associated with reduced risk of colorectal cancer and postmenopausal breast cancer (7). In addition, there is limited but encouraging epidemiologic data suggesting that increased physical activity may be associated with reduced risk of several other cancers as well (7). Physical activity also exerts anticancer effects in several of our transgenic models, but apparently through very different mechanisms than CR (7). For example, the protective effects of exercise appear to be dependent on p53 gene dosage and independent of IGF-1, based on studies in Apc min mice and Wnt-1 transgenic mice (7,8). A better understanding of the mechanisms underlying the energy balance-cancer link will facilitate the development of novel prevention and treatment strategies for offsetting the effects of obesity on cancer. Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL05-01.