Abstract
This chapter posits that cancer is a complex and multifactorial process as demonstrated by the expression and production of key endocrine and steroid hormones that intermesh with lifestyle factors (physical activity, body size, and diet) in combination to heighten cancer risk. Excess weight has been associated with increased mortality from all cancers combined and for cancers of several specific sites. The prevalence of obesity has reached epidemic levels in many parts of the world; more than 1 billion adults are overweight with a body mass index (BMI) exceeding 25. Overweight and obesity are clinically defined indicators of a disease process characterized by the accumulation of body fat due to an excess of energy intake (nutritional intake) relative to energy expenditure (physical activity). When energy intake exceeds energy expenditure over a prolonged period of time, the result is a positive energy balance (PEB), which leads to the development of obesity. This physical state is ideal for intervention and can be modulated by changes in energy intake, expenditure, or both.
Nutritional intake is a modifiable factor in the energy balance-cancer linkage primarily tested by caloric restriction studies in animals and the effect of energy availability. Restriction of calories by 10 to 40% has been shown to decrease cell proliferation, increasing apoptosis through anti-angiogenic processes. The potent anticancer effect of caloric restriction is clear, but caloric restriction alone is not generally considered to be a feasible strategy for cancer prevention in humans. Identification and development of preventive strategies that “mimic” the anticancer effects of low energy intake are desirable. The independent effect of energy intake on cancer risk has been difficult to estimate because body size and physical activity are strong determinants of total energy expenditure. The mechanisms that account for the inhibitory effects of physical activity on the carcinogenic process are reduction in fat stores, activity related changes in sex-hormone levels, altered immune function, effects in insulin and insulin-like growth factors, reduced free radical generation, and direct effect on the tumor. Epidemiologic evidence posits that the cascade of actions linking overweight and obesity to carcinogenesis are triggered by the endocrine and metabolic system. Perturbations to these systems result in the alterations in the levels of bioavailable growth factors, steroid hormones, and inflammatory markers. Elevated serum concentrations of insulin lead to a state of hyperinsulinemia. This physiological state causes a reduction in insulinlike growth factor-binding proteins and promotes the synthesis and biological activity of insulin-like growth factor (IGF)-I, which regulates cellular growth in response to available energy and nutrients from diet and body reserves. In vitro studies have clearly established that both insulin and IGF-I act as growth factors that promote cell proliferation and inhibit apoptosis. Insulin also affects on the synthesis and biological availability of the male and female sex steroids, including androgens, progesterone, and estrogens. Experimental and clinical evidence also indicates a central role of estrogens and progesterone in regulating cellular differentiation, proliferation, and apoptosis induction. Hyperinsulinemia is also associated with alterations in molecular systems such as endogenous hormones and adipokines that regulate inflammatory responses. Obesity-related dysregulation of adipokines has the ability to contribute to tumorigenesis and tumor invasion via metastatic potential. Given the substantial level of weight gain in industrialized countries in the last two decades, there is great interest in understanding all of the mechanisms by which obesity contributes to the carcinogenic process. Continued focus must be directed to understanding the various relationships between specific nutrients and dietary components and cancer cause and prevention. A reductionist approach is not sufficient for the basic biological mechanisms underlying the effect of diet and physical activity on cancer. The joint association between energy balance and cancer risk are hypothesized to share the same underlying mechanisms, the amplification of chemical mediators that modulate cancer risk depending on the responsiveness to those hormones to the target tissue of interest. Disentangling the connection between obesity, the insulin-IGF axis, endogenous hormones, inflammatory markers, and their molecular interaction is vital.
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Fair, A.M., Montgomery, K. (2009). Energy Balance, Physical Activity, and Cancer Risk. In: Verma, M. (eds) Cancer Epidemiology. Methods in Molecular Biology, vol 472. Humana Press. https://doi.org/10.1007/978-1-60327-492-0_3
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