The involvement of the insulin-like growth factors (IGF1, IGF2) in cancer biology has been the focus of extensive research. Ligand-dependent activation of the IGF1 receptor (IGF1-R) has been identified as a crucial step in cancer development. Epidemiological studies revealed that moderately elevated serum IGF1 is associated with increased occurrence of various tumours, including breast, prostate, and colorectal cancer. The IGF1-R is expressed in most transformed cells, where it displays potent antiapoptotic and cell-survival activities. The central role of the IGF1-R in cancer biology is illustrated by studies showing that IGF1-R blockade inhibits tumour growth and angiogenesis. Regulation of IGF1-R gene expression and activity is an important mechanism that allows the cell to decide whether to go into arrest, to proliferate, or to apoptose. IGF1-R levels are controlled by secreted factors of endocrine or local (autocrine/paracrine) origin that can either stimulate or inhibit IGF1-R biosynthesis. In addition, a number of nuclear proteins with oncogenic or antioncogenic properties have been identified that regulate IGF1-R gene transcription. Transcription factors with tumour suppressor activity, such as p53, BRCA1, Von-Hippel Lindau (VHL), and Wilms tumor-1 (WT1), negatively regulate IGF1-R expression. The etiology of neoplasias associated with loss-of-function mutation of tumour suppressors is, in many cases, linked to the inability of mutant forms to suppress their molecular targets, including the IGF1-R gene. Gain-of-function mutations of oncogenes are associated with increased transactivation of the IGF1-R promoter and/or augmented phosphorylation of its cytoplasmic domain and downstream signalling molecules. Interactions between stimulatory and inhibitory factors may ultimately determine the level of expression of the IGF1-R gene and, consequently, the proliferative status of the cell. Understanding the molecular basis of these interactions will be of significant value both in basic as well as in clinical terms.
25 - 29 Apr 2009
European Society of Endocrinology