Insulin-Like Growth Factor System and Sporadic Malignant Melanoma

Abstract

Insulin and insulin-like growth factors (IGFsMelanoma is a malignant tumor originating from melanocytes, the melanin-producing cells.1,2 During fetal development, melanocytes migrate to different body areas, such as the skin, uvea, leptomeninges, and mucous membranes (eg, upper esophagus, vulva, and anus).2 Although melanoma may arise in all these sites, cutaneous melanoma is by far the most frequent type of melanoma, representing approximately 5% to 7% of all skin malignancies and the most lethal skin cancer (approximately 75% of all deaths from skin tumors).2,3 The following melanoma risk factors have been extensively described: i) sun exposure, ii) presence of dysplastic nevi, iii) age, iv) ethnicity, v) personal or family history of melanoma, vi) phototype, vii) presence of xeroderma pigmentosum, viii) Li-Fraumeni syndrome, ix) hereditary retinoblastoma history, and x) immunosuppressive conditions. 4 In addition to environmental and individual risk factors, the genetic pedigree may also represent a further risk factor for melanoma development; indeed, multiple differences between melanoma cell genomes and those of normal melanocytes were identified in genomewide analysis studies. In particular, point mutations, deletions, gene amplifications and translocations, and/or epigenetic modifications (eg, promoter hypermethylation) appear to be associated with a significant growth advantage, as opposed to normal skin cells. 5 Furthermore, many molecular changes have been reported in advanced stages of melanoma, as opposed to normal melanocytes. The most common mutations are as follows: i) protoncogene serine/threonine kinase B-Raf-activating mutations, 6 ii) E-cadherin expression silencing, 7 and iii) telomerase activity acquisition, 8 followed by hundreds more, identified by comparative gene expression profiling of melanomas with various American Joint Committee on Cancer stages. 1,9,10 A recent article by Bennet 1 provided a detailed list of possible genes involved in melanoma spreading and development.Along with all pathways and molecules studied in different cancers, including melanoma itself, the study of the insulin-like growth factor (IGF) network of ligands, cell surface receptors, and IGF-binding proteins (IGFBPs; eg, the IGF-1 system) have attracted considerable interest because these pathways play important roles at multiple levels, from cellular and organ to organism.11-13 The IGF system mediates growth, differentiation, and developmental processes; it is involved in a variety of metabolic activities.13 Deregulation of IGF system expression and action is linked to several pathological features, ranging from growth deficits to cancer development. TarSupported by the Italian Health Ministry (code ONC_ORD3207) and Programma strategico 3: Diagnostica ad elevata complessità e tecnologie per il monitoraggio di pazienti con patologie croniche-PROGETTO 4_ISS.Accepted for publication August 10, 2010. CME Disclosure: The author did not disclose any relevant financial relationships.Address reprint requests to Ettor...

Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways

“…We did not detect any endogenous insulin or IGF2 RNA or protein levels in any of the four melanoma cells tested, but our RT-qPCR studies revealed presence of IGF1 RNA that is supported by recent reports [68]. IGF1 & IGF2 and their cognate receptors are important regulators of multiple human cancers, including melanoma [67, 100–103]. We found high levels of RNA of the corresponding cognate receptors – IR, IGF1R, and IGF2R in all the four melanoma cells studied here.…”

Aberrant allele-switch imprinting of a novel IGF1R intragenic antisense non-coding RNA in breast cancers

“…The insulinlike growth factor system, including the type I IGF receptor IGF1R and the mitogenic ligands IGF-I and IGF-II, is frequently dysregulated in breast cancer and is known to contribute to disease progression and metastasis [10][11][12][13][14]. IGF-I and IGF-II promote cell growth and survival via the IGF1R receptor-mediated signal transduction through intracellular tyrosine kinase linked to the phosphatidyl-inositol-3 kinase (PI3K)-Aktmammalian target of rapamycin (mTOR) pathway.…”

“…Overexpression of IGF1R activates the PI3-K and mitogen-activated protein kinases (MAPK) signal cascades, resulting in cell proliferation and resistance to chemotherapeutic agents, radiation, and targeted therapies using Tamoxifen and Herceptin [15][16][17]. Therapeutic agents targeting IGF1R are currently in clinical development [10][11][12][13][14][18][19][20][21][22][23], including those that inhibit the IGF1R tyrosine kinase using monoclonal antibodies and small molecules [24]. However, the clinical development of various IGF1R inhibitors has been put on hold due to lack of sufficient clinical efficacy.…”

The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice

“…We showed in this study that HNG not only inhibited plasma IGF-1 levels but also enhanced the CPinduced suppression of IGF-1 in tumor-bearing mice. The decrease of IGF-1 by HNG may inhibit IGF-1 bio-availability to its receptor leading to the suppression of melanoma growth (48). It is worth noting that strategies using blocking antibodies against IGF-1 receptor were not successful because of lack of efficacy and increased side effects; these were likely related to the increase in GH levels with IGF-1 receptor blockade which is not induced by fasting or humanin treatment (45,49).…”