Editorial [Hot Topic: Targeting the IGF-I Receptor Signaling Pathway:Implications for Human Cancer Therapy (Executive Editors: A. Ciampolillo and F. Giorgino) ]

A common molecular abnormality in human cancer is the presence of multiple autocrine loops, with one of the most prominent involving co-expression of insulin-like growth factor-I (IGF-I) and its receptor. Epidemiological studies have shown that increased serum levels of IGF-I and decreased levels of its predominant binding protein, IGFBP-3, correlate with an increased risk for several types of cancers. IGF-I has also been shown to be an important regulator of VEGF expression and angiogenesis in several cancers. In writing this review issue, we have sought to provide an updated overview on the role of IGFs and the IGF-I receptor signaling pathway in human cancer.

The first article by Laviola et al. [1] provides a general overview on IGF-I receptor structure and function, its intracellular signaling pathways, and some important implications deriving from the activation of the IGF-I signal transduction system in specific tissues (e.g., skeletal muscle, heart, brain, beta-cells). In particular, novel actions resulting from activation of the PI 3- kinase/Akt cascade by the IGFs are illustrated, including promotion of survival of cardiac myocytes both in vitro and in vivo, protection of cells from reperfusion injury in vivo, and preservation of myocardial function. Moreover, the effects of IGF-I on the neuronal tissue are described with particular emphasis on IGF-I regulation of brain development, neuronal survival, and synaptogenesis during early postnatal life. Finally, the role of the IGF system in the beta-cells is also described, including the modulatory effects on insulin secretion and the regulation of early islet development and hypertrophic response to insulin resistance or pancreatic injury.

The article by Belfiore [2] focuses on the emerging role of the IGF-I receptor homolog receptor, the insulin receptor (IR), in cancer. In fact, several epidemiological studies have shown that insulin resistance states are characterized by hyperinsulinemia, and are associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon, and kidney. IR is overexpressed in several human malignancies, and this occurs by multiple mechanisms. Interestingly, one of the two IR isoform (IR-A) is specifically overexpressed in cancer cells. IR-A is the fetal isoform of the IR and has the peculiar characteristic to bind and to be activated not only by insulin but also by IGF-II. Overexpression of the IR-A has thus emerged as a major mechanism of IGF system overactivation in cancer. These findings may have important implications for both the prevention and treatment of the most frequent forms of cancer.

Varela-Nieto et al. [3] discuss the mechanisms of IGF-I survival actions in development. The developing inner ear is taken as a model system to study the anti-apoptotic actions of the IGF system. The inner ear is a complex sensory organ responsible for equilibrium and sound detection in vertebrates. IGF-I is expressed during the early embryonic development in the otic vesicle and in neuroblasts destined to generate the auditory ganglia. Interference of endogenous IGF-I activity impairs survival, proliferation, and differentiation of the otic neuroblasts, suggesting that survival promotion is the main activity of this factor. Moreover, the biological activities of ectopic IGF-I are described in avian cell systems. The mitogenic and anti-apoptotic functions of IGF-I become apparent upon ectopic expression in primary avian fibroblasts in which this growth hormone enhances cell proliferation and allows cells to escape from apoptosis induced by low serum concentrations. These experiments have suggested that IGF-I cannot be regarded as a typical oncoprotein but rather as a growth factor inducing mitogenesis and ensuring cell survival in stress situations, and as a tumor promoter in cells with aberrant IGF signaling.

The review article by Scisci and Surmacz [4] focuses on the crosstalk between the IGF system and several steroid hormones (e.g., estrogens, progestins and androgens) implicated in the pathogenesis of breast cancer. The biological effects of steroid hormones are mediated by their cognate receptors, which are members of the nuclear receptors superfamily of transcriptional activators........