Insulin-like growth factor system in growth, development and carcinogenesis

IGF-I and IGF-II are polypeptides with significant homology to proinsulin that exert growth-regulatory and differentiation effects on several cell types throughout the life span of animals. At least three receptors (R), IGF-I-R, IGF-II-R and insulin R (IR) mediate biological effects of insulin-like growth factors (IGFs). IGFs are potentially available to the cells via autocrine, endocrine, and paracrine pathways, making them some of the most available growth factors in the microenvironment of cells. IGF-I-R and IR are tyrosine kinase receptors and mediate growth and metabolic effects of IGFs. IGF-II-R preferentially bind IGF-II, followed by internalization and degradation of the peptide. Biological effects of IGF-II are thus dictated by stoichiometric expression of IGF-I-R vs IGF-II-R. IGF binding proteins (BP-1-6) have a high binding affinity for IGFs and regulate their bio-efficacy. Regulatory function of BPs is further modulated by IGFBP proteinases and "receptor-like" proteins that bind BPs, resulting in IGF independent effects of BPs. The availability of BPs, as either intact, bound, or proteolytic forms, can significantly modulate the final biological action of IGFs. Thus, the IGF system includes IGFs, IGF receptors, IGFBPs, IGFBP proteinases, and IGFBP-binding proteins (receptors?). IGFs are being increasingly recognized as a major regulatory force in health and disease by cancer biologists, endocrinologists, neuroscientists, and physiologists and are currently being used for diagnostic, prognostic, and therapeutic purposes. In this review, we will outline recent developments in this field with an emphasis on cancer.