Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface protein that is evolutionarily related to the insulin receptor (InsR). The effects of IGF1 are moderated by a group of binding proteins (IGFBPs) that bind and transport the ligand in the circulation and extracellular fluids. In mechanistic terms, IGF1R function is linked to the MAPK and PI3K signaling pathways. Furthermore, IGF1R has been shown to migrate to cell nucleus, where it functions as a transcriptional activator. The co-localization of IGF1R and MAPK in the nucleus is of major interest as it suggests novel mechanistic paradigms for the IGF1R-MAPK network. Given its potent anti-apoptotic and pro-survival roles, and in view of its almost universal pattern of expression in most types of cancer, IGF1R has emerged as a promising molecular target in oncology. The present review article provides a concise overview of key scientific developments in the research area of IGF and highlights a number of more recent findings, including its nuclear migration and its interaction with oncogenes and tumor suppressors.

Background: Insulin analogues are widely used in the treatment of diabetes mellitus. Some insulin analogues were reported to display atypical activities in vitro that resemble those of insulin‐like growth factor‐I (IGF‐I). The aim of this study was to investigate whether two long‐acting insulin analogues [glargine (Lantus, Sanofi Aventis, Germany) and detemir (Levemir, Novo Nordisk, Denmark)] and two short‐acting analogues [lispro (Humalog, Eli Lilly, Indianapolis, USA) and aspart (Novolog, Novo Nordisk, Denmark)] exhibit IGF‐I‐like activities on cultured cancer cells in comparison with IGF‐I and regular human insulin.Methods: HCT‐116 (colorectal cancer), PC‐3 (prostate cancer) and MCF‐7 (breast adenocarcinoma) cell lines were treated with insulin, IGF‐I or insulin analogues, and proliferation and protection from apoptosis were measured by cell counting and fluorescent‐activated cell sorter (FACS) analysis, respectively. In addition, Western blots were used to identify signalling molecules activated by the analogues.Results: Glargine, detemir and lispro had proliferative effects that resemble IGF‐I action. Insulin, however, did not stimulate cellular proliferation. In addition, glargine and detemir displayed an IGF‐I‐like anti‐apoptotic activity. Glargine, like insulin and IGF‐I, induced phosphorylation of both ERK and AKT, suggesting that the analogue is able to stimulate both the ras‐raf‐mitogen‐activated protein kinase (MAPK) and PI3K‐AKT pathways. Furthermore, glargine induced both insulin receptor (IR) and IGF‐IR phosphorylation.Conclusions: Glargine, detemir and lispro, unlike regular insulin, exhibit in vitro proliferative and anti‐apoptotic activities in a number of cancer cell lines. These actions resemble some of the effects of IGF‐I, a growth factor involved in cancer initiation and progression. Insulin had no increased IGF‐I activity. The specific receptor/s involved in mediating analogues actions remains to be identified. Copyright © 2009 John Wiley & Sons, Ltd.

The insulin-like growth factor-I receptor (IGF-IR) mediates the biological actions of both IGF-I and IGF-II. The IGF-IR is expressed in most transformed cells, where it displays potent antiapoptotic, cell-survival, and transforming activities. IGF-IR expression is a fundamental prerequisite for the acquisition of a malignant phenotype, as suggested by the finding that IGF-IR-null cells (derived from IGF-IR knock-out embryos) are unable to undergo transformation when exposed to cellular or viral oncogenes. This review article will focus on the underlying molecular mechanisms that are responsible for the normal, physiological control of IGF-IR gene expression, as well as the cellular pathways that underlie its aberrant expression in cancer. Examples from the clinics will be presented, including a description of how the IGF system is involved in breast, prostate, pediatric, and gynecological cancers. Finally, current attempts to target the IGF-IR as a therapeutic approach will be described.

Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

Insulin and the insulin-like growth factors (IGF-I, IGF-II) are pleiotropic hormones that have multiple roles in regulating vital metabolic and developmental processes. Although most early data suggested that insulin is mainly involved in metabolic activities (e.g. control of sugar levels) and IGF-I/II control growth and differentiation events (e.g. bone elongation, cell division), today, it is clear that there is cross-talk between the various ligands and receptors of the IGF family. As a result of these complex interactions, the spectrum of activities that were classically assigned to insulin or IGF-I/II has greatly expanded, and the signalling events mediated by the insulin and IGF receptors is the subject of intensive research. This review provides a comparative analysis of the structures, receptors, and signalling pathways of insulin and IGF-I.