Endocrine Abstracts

Epidemiological observations increasingly imply nutritional energy balance as a key risk factor for cancer development. Excess body weight is associated with increased risks of cancers of the endometrium, breast (postmenopausal women), kidney (renal cell tumours), colon, pancreas and oesophagus (adenocarcinomas). By contrast, regular physical activity reduces the risk of developing breast and colorectal cancers, and potentially other tumour types. Overall, excess weight and lack of physical activity may account for one quarter to half of the occurrence of the abovementioned tumour types.

The mechanisms that may underlie these relationships of nutritional energy balance with cancer development may depend on tumour type.

One major mechanism that is increasingly being implicated is alterations in the metabolism of insulin and/or insulin-like growth factors (IGFs) are as possible metabolic links between nutritional energy balance and cancer development. Prospective cohort studies have shown increased risks particularly of colon cancer and endometrial cancer among women and men with high fasting and non-fasting plasma insulin concentrations, and similar associations have been reported for pancreas cancer. Likewise, elevated plasma concentrations of IGF-I have been related to increased risks of cancers of the prostate, breast and colorectum. More independently of adiposity, higher plasma glucose levels (fasting and post-load) have also been associated with increased risks of cancers of the pancreas, liver and endometrium, in particular, as well as of the colon. Finally, there is increasing evidence to suggest that adiposity may also promote tumor development through the release of pro-inflammatory adipokines and cytokines, creating a state of chronic, low-grade inflammation.

In addition to insulin, IGF-I and glucose, endogenous sex hormones are strongly implicated in the development of cancers of the endometrium and breast, and especially among postmenopausal women that are overweight or obese. Among premenopausal women, development of ovarian hyperandrogenism (polycystic ovary syndrome) is a frequent phenomenon that is related to obesity and hyperinsulinaemia, which is associated with an increased risk of endometrial cancer because of reduced ovarian progesterone synthesis.

Besides the extracellular growth signals, there is increasing experimental evidence that intracellular energy sensing mechanisms are also central in controlling cell growth, proliferation and apoptosis. One mechanism of special interest, here, is the suppression of AMP-activated kinase (AMPK) activity, as a result of higher energy status of the cell.

Gaining a better understanding of the mechanisms relating excess weight and physical inactivity to cancer may lead to improved strategies for both cancer prevention and treatment.