MOLECULAR BIOLOGY OF THE INSULIN-LIKE GROWTH FACTOR SYSTEM
The insulin-like growth factors (IGF1, IGF2) are a family of hormones with important roles in growth and development. The biological actions of the IGFs are mediated by the IGF1 receptor (IGF1R), a cell-surface, tyrosine kinase-containing receptor, which is structurally and evolutionarily related to the insulin receptor. The IGF1R signaling pathway has an important role in the biochemical chain of events linking obesity, diabetes, and cancer. Our work is aimed at understanding the transcriptional and epigenetic events responsible for IGF1R expression under physiological and pathological conditions. These studies are expected to generate information that might translate into more efficient IGF1R targeting approaches in cancer and, potentially, other conditions in which the IGF axis is involved. A better understanding of the molecular biology of the IGF system will have important ramifications in areas such as growth and development, obesity, diabetes, and cancer research.
The IGF1R plays an important role in protection from apoptosis, regulation of cell growth, differentiation and oncogenic transformation. IGF1R aberrations lead to intrauterine and postnatal growth failure, microcephaly, mental retardation and deafness. High levels of IGF1R are detected in a diversity of human tumors. IGF1R gene transcription is controlled by complex interactions involving DNA-binding and non DNA-binding transcription factors. We have identified a series of tumor suppressors, including the breast cancer gene-1 (BRCA1), p53, the Wilm’s tumor protein-1 (WT1) and the von Hippel-Lindau gene (VHL), whose mechanisms of action involve regulation ofIGF1R gene expression. IGF1R gene transcription is also dependent on the presence of stimulatory nuclear proteins, including zinc-finger protein Sp1, EWS-WT1, E2F1, Krüppel-like factor-6 (KLF6), high-mobility group A1 (HMGA1), and others. Loss-of-function of tumor suppressor genes, usually caused by cancer-specific mutations, may result in non-functional proteins unable to control IGF1R promoter activity. Impaired regulation of the IGF1R gene is linked to defective cell division, chromosomal instability and increased incidence of cancer.
Tumor specific translocations that disrupt the architecture of transcription factors are a common theme in oncogenesis. As a result of these rearrangements, chimeric proteins are generated that are composed of modules derived from unrelated genes. Most classical examples of aberrant chimeras exist in the fields of pediatric and hematological oncology. Using a bioinformatic approach aimed at discovering candidate oncogenic chromosomal aberrations on the basis of outlier gene expression, Dr. A. M. Chinnaiyan reported the identification of recurrent gene fusions of the 5’ untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer. ERG was identified as the most commonly overexpressed oncogene in prostate cancer. Fusion of ERG toTMPRSS2 was seen in 90% of the cases, suggesting that the fusion event was the most likely cause for ETS overexpression. Studies in our laboratory are aimed to identify theIGF1R promoter as a biologically relevant downstream target of disrupted transcription factor TMPRSS2-ERG in prostate cancer.
The specificity of the insulin receptor (InsR) and IGF1R signaling pathways has been the focus of significant debate over the past few years. Recent evidence showing nuclear import and a direct transcriptional role for both InsR and IGF1R adds a new layer of complexity to this dialogue. Hence, in addition to the classical roles associated with cell-surface receptors (e.g., ligand binding, autophosphorylation of the tyrosine kinase domain, activation of IRS-1 and additional substrates, protein-protein interactions with membrane and cytoplasm components, etc) new data is consistent with nuclear (genomic) role/s for both InsR and IGF1R. The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. While research on the role of nuclear InsR/IGF1R is still at its infancy, we believe that this rapidly developing area may have a major basic and translational impact in the fields of metabolism, diabetes and cancer.
The IGF signaling pathways have been implicated in the etiology of a number of epithelial neoplasms including prostate, breast, colon and more recently, gynecologic cancers. The IGF1R is expressed in most transformed cells, where it displays potent anti-apoptotic, cell-survival and potentially, transforming activities. IGF1R expression and activation are typical hallmarks associated with tumor initiation and progression. Multiple approaches have been used to abrogate IGF1R signaling for targeted cancer therapy including antibodies and small molecule tyrosine kinase inhibitors. These novel IGF1R targeting agents have produced significant experimental and clinical results in many cancers and generated considerable optimism in the field of cancer therapy. A better understanding of the complex mechanisms underlying the regulation of the IGF system will improve our ability to develop effective treatment modalities for malignancies in which the IGF axis is involved.
Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is a form of dwarfism caused by deletion or mutation of the GH receptor (GH-R) gene, leading to congenital IGF1 deficiency. This genetic (autosomal recessive with full penetrance) entity was identified in Israel in the 1950s by Prof. Zvi Laron in three siblings of Yemenite origin and reported in 1966. The typical features of LS are short stature of -4 to -10 SDS below the median normal height, typical face, obesity, high basal serum GH, and low serum IGF1, unresponsive to the administration of exogenous GH. The recognition that an inherited mutant GH-R gene is the etiological factor behind LS was first reported in 1989.
Recent epidemiological studies revealed that LS patients, but not family members, are protected from cancer development. The finding that congenital IGF1 deficient patients do not develop cancer (up to the age of 85) is of an exceptional clinical and scientific value. The interpretation of epidemiological data is consistent with the notion that homozygous congenital IGF1 deficiency, or deficiency in early childhood, may confer protection against future development of cancer. This ‘experiment of nature’emphasizes the central role of the IGF1 hormonal axis in cancer development and justifies the rational use of available post-genomic technologies in order to elucidate in an unbiased fashion the molecular basis that underlies the evasion of LS patients from cancer.
Insulin analogues have been developed to achieve a more physiological replacement of insulin, making a major impact on diabetes therapy. Modifications in the amino acid sequence of the insulin molecule changed the pharmacokinetic and pharmacodynamic properties of the analogues with respect to human insulin. It appears, however, that these changes also modified the molecular and biological effects of the analogues, thereby enhancing their affinity for the IGF1R. The IGF1R, which resembles the insulin receptor, has an important role in the development and progression of many different human cancers. In addition, recent large epidemiological studies have suggested that certain insulin analogues might be involved in cancer development and/or progression. In particular, epidemiological data has been presented linking the use of long-acting analogue glargine with an enhanced cancer risk compared with regular insulin. Studies in our laboratory are designed to evaluate the hypothesis that the atypical mitogenic and signalling activities elicited by insulin analogues may have a marked impact on tumour behavior.