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• W2005946187 abstract "The inherent ability of a cell to undergo apoptosis governs a number of developmental processes essential to proper mammalian development. Into adulthood, the pathways that potentiate the apoptotic response are extremely diverse and finely regulated to prevent potential diseases. Of these, cancer is often associated with loss of an apoptotic response. Hanahan and Weinberg, 2000Hanahan D. Weinberg R.A. The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (20563) Google Scholar list evasion of apoptosis as a hallmark feature acquired during neoplastic transformation. The impact of this event is dramatic on several levels; avoidance of apoptosis not only prevents programmed cell death in an array of cell types but also promotes chemotherapeutic resistance during anticancer regimens. The inherent ability of a cell to undergo apoptosis governs a number of developmental processes essential to proper mammalian development. Into adulthood, the pathways that potentiate the apoptotic response are extremely diverse and finely regulated to prevent potential diseases. Of these, cancer is often associated with loss of an apoptotic response. Hanahan and Weinberg, 2000Hanahan D. Weinberg R.A. The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (20563) Google Scholar list evasion of apoptosis as a hallmark feature acquired during neoplastic transformation. The impact of this event is dramatic on several levels; avoidance of apoptosis not only prevents programmed cell death in an array of cell types but also promotes chemotherapeutic resistance during anticancer regimens. In mammalian systems, there are currently 12 known members of the Bcl-2 family of apoptotic regulators (Youle and Strasser, 2008Youle R.J. Strasser A. The BCL-2 protein family: opposing activities that mediate cell death.Nat Rev. 2008; 9: 47-59Crossref Scopus (3227) Google Scholar); this group is divided into anti-apoptotic members (Bcl-2, Bcl-XL, Mcl-1, etc.) and pro-apoptotic proteins (BID, BAX, BAD, NOXA, etc.). A delicate balance of these proteins dictates the fate of a given cell; a rheostat exists between pro- and anti-apoptotic Bcl-2 family members to modulate cell death or survival, whereby whichever is more highly expressed determines the cellular outcome (Oltvai et al., 1993Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.Cell. 1993; 74: 609-619Abstract Full Text PDF PubMed Scopus (5667) Google Scholar). Survivin (encoded by BIRC5) is a member of the inhibitors of apoptosis family of proteins and functions similarly to anti-apoptotic Bcl-2 family members (Altieri, 2008Altieri D.C. Survivin, cancer networks and pathway-directed drug discovery.Nat Rev Cancer. 2008; 8: 61-70Crossref PubMed Scopus (825) Google Scholar). Collectively, these apoptotic proteins control fundamental cell fate decisions that underlie the difference between homeostasis and onset of disease. Metastatic melanoma is a complex malignancy that is refractory to nearly all known chemotherapeutics; as a result of the relative dearth of available therapies, the 5-year survival rate for patients afflicted with metastatic melanoma is approximately 15%. The inherent drug resistance observed in melanoma may be due, in part, to the network of signaling pathways that are activated during malignant transformation (Bennett, 2008Bennett D.C. How to make a melanoma: what do we know of the primary clonal events?.Pigment Cell Melanoma Res. 2008; 21: 27-38Crossref PubMed Scopus (147) Google Scholar). Although the cooperative phenotype that results from activation of these pathways is similar, their individual contributions and overall significance to disease may greatly contrast; thus, it is paramount to understand how each pathway can contribute to disease initiation, progression, and clinical manifestation. The IGF-1 signaling axis originates from the IGF-1 receptor. IGF-1R is a heterotetramer consisting of two extracellular α subunits and two β subunits that encompass the transmembrane and tyrosine kinase domains (Hartog et al., 2007Hartog H. Wesseling J. Boezen H.M. van der Graaf W.T. The insulin-like growth factor 1 receptor in cancer: old focus, new future.Eur J Cancer. 2007; 43: 1895-1904Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). After ligand binding, IGF-1R initiates a series of signaling events that positively affect the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, among others. Because these pathways are commonly activated in a variety of cancers, it is not surprising that a number of monoclonal antibodies and small-molecule inhibitors of IGF-1R are currently in clinical development (Hartog et al., 2007Hartog H. Wesseling J. Boezen H.M. van der Graaf W.T. The insulin-like growth factor 1 receptor in cancer: old focus, new future.Eur J Cancer. 2007; 43: 1895-1904Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Somewhat surprisingly, IGF-1 is not expressed in melanoma cells (Rodeck et al., 1991Rodeck U. Melber K. Kath R. Menssen H.D. Varello M. Atkinson B. et al.Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes.J Invest Dermatol. 1991; 97: 20-26Abstract Full Text PDF PubMed Google Scholar); however, IGF-1R expression is correlated with melanoma progression (Kanter-Lewensohn et al., 2000Kanter-Lewensohn L. Dricu A. Girnita L. Wejde J. Larsson O. Expression of insulin-like growth factor-1 receptor (IGF-1R) and p27Kip1 in melanocytic tumors: a potential regulatory role of IGF-1 pathway in distribution of p27Kip1 between different cyclins.Growth Factors. 2000; 17: 193-202Crossref PubMed Scopus (58) Google Scholar). These observations suggest that paracrine-derived signals may be responsible for activation of IGF-1R during advancement of melanocytic disease. Indeed, our laboratory previously demonstrated that fibroblast-derived IGF-1 promotes growth and survival of early-stage melanoma cells (Satyamoorthy et al., 2001Satyamoorthy K. Li G. Vaidya B. Patel D. Herlyn M. Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways.Cancer Res. 2001; 61: 7318-7324PubMed Google Scholar). In this issue, Hilmi et al., 2008Hilmi C. Larribere L. Giuliano S. Bille K. Ortonne J.-P. Ballotti R. et al.IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin.J Invest Dermatol. 2008; 128: 1499-1505Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar bolster a role for IGF-1 in melanoma pathophysiology by revealing that resistance to apoptosis in melanoma may be due to IGF-1-mediated expression of the anti-apoptotic proteins Bcl-2, Bcl-XL, and survivin (Hilmi et al., 2008Hilmi C. Larribere L. Giuliano S. Bille K. Ortonne J.-P. Ballotti R. et al.IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin.J Invest Dermatol. 2008; 128: 1499-1505Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). The results from this study shed additional light on the mechanisms by which microenvironmental influences promote the chemoresistant phenotype associated with most advanced-stage melanomas. Using two melanoma cell lines (MeWo and A375), the authors demonstrated that IGF-1 is sufficient to inhibit tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis; this antagonistic effect appeared to bypass caspase-8 activation and, instead, was dependent on caspases-9 and -3. This latter observation is intriguing because TRAIL is generally thought to induce apoptosis through a binding event with an appropriate death receptor, thereby initiating the “extrinsic” apoptotic pathway characterized by caspase-8 activation; here, caspases-3 and -9 were activated rather than caspase-8. These caspases (9 and 3) are associated with the “intrinsic” pathway that is affiliated with compromised mitochondrial function. Experiments measuring mitochondrial membrane potential validated those data and supported the premise that IGF-1 rescues TRAIL-induced apoptosis via prevention of the intrinsic apoptotic signaling cascade. Finally, upregulation of the anti-apoptotic proteins Bcl-2, Bcl-XL, and survivin was provided as the mechanistic evidence for the biological effects of IGF-1. Previous studies have demonstrated a role for IGF-1 in the proliferation of early-stage melanoma cells but not metastatic melanomas (Satyamoorthy et al., 2001Satyamoorthy K. Li G. Vaidya B. Patel D. Herlyn M. Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways.Cancer Res. 2001; 61: 7318-7324PubMed Google Scholar), suggesting that IGF-1 has little effect on melanoma growth after the radial-growth phase of disease; this new report assigns a novel role to IGF-1 during disease progression: evasion of apoptosis. The malignant phenotype of melanoma is undeniably resistant to an assortment of anticancer therapeutics. The mechanisms responsible for drug resistance in melanoma are likely not limited to a single pathway or effector; instead, the chemoresistant nature of melanomas is probably the additive result of a number of drug efflux pumps, activation of cell survival pathways, and, potentially, the presence of a slow-cycling tumor-initiating cell population. The IGF-1 growth factor is now described as another potential mediator of cell survival in melanoma, thereby implicating IGF-1 signaling in additional biomolecular processes essential for maintenance of disease. The precise cell type that produces IGF-1 in the tumor microenvironment is still uncertain. It is apparent that melanoma cells themselves express minimal amounts of IGF-1, indicating that the presence of IGF-1 is from a paracrine source. Others have suggested that stromal components are responsible for IGF-1 production in other cancer lesions (Cullen et al., 1991Cullen K.J. Smith H.S. Hill S. Rosen N. Lippman M.E. Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions.Cancer Res. 1991; 51: 4978-4985PubMed Google Scholar; van der Laan et al., 1995van der Laan B.F. Freeman J.L. Asa S.L. Expression of growth factors and growth factor receptors in normal and tumorous human thyroid tissues.Thyroid. 1995; 5: 67-73Crossref PubMed Scopus (92) Google Scholar), and melanoma appears to be no different. Our laboratory has extensive gene expression data for a large panel of melanoma cell lines; Figure 1 depicts the expression profiles of the target genes of IGF-1 signaling (Bcl-2, Bcl-XL, and survivin), as described by Hilmi et al. Our data suggest that the expression of these survival factors varies greatly across melanoma samples, rather than being highly expressed; the apparent discrepancy between our data and those reported by Hilmi et al. may be due to one of several factors. First, the authors used only two cell lines in their studies, which might have not been enough lines to accurately predict a similar association across a larger sample size. Next, our gene expression profiling was performed in the continued presence of excess (5 μg/ml) insulin, rather than a transient treatment with IGF-1 to serum-starved cells; this minor experimental difference could account for the discrepancy between the two sets of data. Although the results of Hilmi et al., 2008Hilmi C. Larribere L. Giuliano S. Bille K. Ortonne J.-P. Ballotti R. et al.IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin.J Invest Dermatol. 2008; 128: 1499-1505Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar help to establish a role for IGF-1 signaling in expression of anti-apoptotic molecules, they leave other questions unanswered. For example, what are the molecular mechanisms by which IGF-1 is able to induce expression of Bcl-2, Bcl-XL, and survivin—are these proteins coregulated or similarly affected by distinct downstream mediators of the IGF-1 signaling axis? Likewise, MeWo and A375 cells represent metastatic melanomas—is the prosurvival phenotype after IGF-1 treatment a function of disease stage or is this observation merely coincidental? Furthermore, does inhibition of IGF-1 signaling (via IGF-1R monoclonal antibodies, for example) synergize with traditional chemotherapeutics to initiate disease regression? These types of studies appear promising in preclinical investigations (Ji et al., 2007Ji Q.S. Mulvihill M.J. Rosenfeld-Franklin M. Cooke A. Feng L. Mak G. et al.A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo.Mol Cancer Ther. 2007; 6: 2158-2167Crossref PubMed Scopus (124) Google Scholar; Maloney et al., 2003Maloney E.K. McLaughlin J.L. Dagdigian N.E. Garrett L.M. Connors K.M. Zhou X.M. et al.An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation.Cancer Res. 2003; 63: 5073-5083PubMed Google Scholar), whereas results from early clinical trials are still pending. The authors state no conflict of interest." @default.
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• W2005946187 title "Unraveling the Mysteries of IGF-1 Signaling in Melanoma" @default.
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