Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression

Abstract

The insulin-like growth factors (IGFs) are mitogens that play a pivotal role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-I receptor, which is also involved in cell transformation induced by tumor virus proteins and oncogene products. Six IGF-binding proteins (IGFBPs) can inhibit or enhance the actions of IGFs. These opposing effects are determined by the structures of the binding proteins. The effects of IGFBPs on IGFs are regulated in part by IGFBP proteases. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiologic studies, which have found that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with increased risk of several common cancers, including those of the prostate, breast, colorectum, and lung. Evidence further suggests that certain lifestyles, such as one involving a high-energy diet, may increase IGF-I levels, a finding that is supported by animal experiments indicating that IGFs may abolish the inhibitory effect of energy restriction on cancer growth. Further investigation of the role of IGFs in linking high energy intake, increased cell proliferation, suppression of apoptosis, and increased cancer risk may provide new insights into the etiology of cancer and lead to new strategies for cancer prevention.

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

“…The insulin-like growth factor 1 receptor (IGF-1R), a tetrameric receptor tyrosine kinase (RTK), is important for transformation, proliferation of malignant cells (Baserga, 1995;Baserga et al, 1997;Adams et al, 2000;LeRoith and Roberts, 2003;Larsson et al, 2005), crucial for preventing apoptosis, maintaining malignant phenotype and for resistance to chemotherapy (Baserga, 1995(Baserga, , 2000Yu and Rohan, 2000;Samani et al, 2007).…”

C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

“…Both peptides activate growth-promoting signal transduction pathways by interacting with their receptors, and, to some extent, can also bind to their mutual receptors or to hybrid insulin/IGF-I receptors [9,10]. Other common effects include stimulation of sex steroid synthesis [41][42][43][44][45] and inhibition of SHBG production [24,26,46].…”

“…In vitro studies have shown that insulin, IGF-I and sex-steroid hormones all promote cell growth and proliferation, and serum levels of these hormones have been associated with cancer risk [5,[9][10][11]. Evaluation of interrelationships between these hormones and their associations with adiposity may therefore provide information about the role of hormones in the association between excess weight and cancer risk.…”

Body mass index, waist circumference and waist–hip ratio and serum levels of IGF-I and IGFBP-3 in European women

“…6 In blood circulation, over 75% of IGF-I is bound to the insulin-like binding protein (IGFBP)-3. 7 Circulating IGF-I levels are largely determined by genetic factors and age, 8,9 and are also affected by sex, anthropometric indices, physical activity, exogenous sex hormones, smoking, alcohol consumption 10 and nutritional status. 6 Circulating levels of IGF-I and IGFBP-3 concentrations vary considerably between normal individuals, but blood levels in each individual are relatively constant.…”