Endocrine Abstracts

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.