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The Molecular Pathology of Cutaneous Melanoma

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The Molecular Pathology of Cutaneous Melanoma Cancer Biomarkers 9 (2011) 267–286 267 DOI 10.3233/CBM-2011-0164 IOS Press The molecular pathology of cutaneous melanoma Thomas Bogenriedera and Meenhard Herlynb,∗ aBoehringer Ingelheim RCV, Dr. Boehringer Gasse 5-11, 1121 Vienna, Austria bThe Wistar Institute, 3601 Spruce Street, Philadelphia, PA, USA Abstract. Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogen- associated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit from agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease. Keywords: Melanoma, cell cycle, pRb pathway, p16INK4A, p14ARF, cyclins, CDKs, Apaf1, Bcl2, MAPK pathway, Ras, BRAF, PTEN, PI3K/AKTpathway, SCF, ckit, HGF, cmet, cmyc, Notch 1. Introduction mately lead to more successful therapeutic strategies. The goal of this chapter, therefore, is to highlight some As the treatment of metastatic melanoma moves of the issues that have arisen. For the purpose of this rapidly into the era of targeted therapy, there is an chapter we will focus on the molecular events occurring ever growing need to untangle the underlying genet- within the melanoma cell, especially those pathways ic complexity and cellular signalling heterogeneity of which have been the scope of intensive research over the this highly malignant tumor. It is widely hoped that past decade and which are now targets of an increasing an understanding of how genetic and signalling profiles armamentarium of novel therapeutic approaches. Here, dictate pharmacologic response will allow for the se- we discuss recent findings and hypotheses on the role lection of optimal patient sub-populations for clinical of growth factor pathways in the molecular pathology trials. of melanoma. The matter of melanoma-stroma interac- The molecular pathology of melanoma development tions is too involved to thoroughly explore here. As the and progression is now being deciphered (Fig. 1). Al- literature on molecular and cellular events in melanoma though we have an increasingly good understanding of development and progression is now huge and includes the genetics and biochemistry of these events,the mech- anisms underlying their combinatorial interactions are comprehensive reviews [1–5], we will take the liberty still poorly defined and need to be fathomed to ulti- of a more subjective view and review molecules and pathways that now take center stage as well as dis- cuss emerging areas and interesting questions in the ∗Corresponding author. E-mail: [email protected]. melanoma field. ISSN 1574-0153/11/$27.50 2011 – IOS Press and the authors. All rights reserved 268 T. Bogenrieder and M. Herlyn / The molecular pathology of cutaneous melanoma Fig. 1. Development of melanoma. This model implies that melanoma commonly develops and progresses in a sequence of steps from nevic lesions, which can be histologically identified in approximately 35% of cases. The model also acknowledges that melanoma may also develop directly from normal cells. The exact role of tumor-initiating or melanoma stem cells remains to be elucidated. Genetic (such as mutations and deletions of critical genes) and epigenetic (such as DNA-methylation leading to gene silencing) alterations of critical pathways as well as the acquired capability of evading apoptosis, progressively disturb normal skin homeostatis leading to melanoma development. Genetic changes are expected at the transition from common acquired (benign) nevus to dysplastic nevus and primary melanoma allowing cells to persist. During melanoma invasion and metastasis increased growth, invasion and stromal ‘landscaping’ by proteolysis occurs, leading to an increased manipulation of the microenvironment and interactions with stromal skin cells. 2. The unmet clinical need: “Melanoma is the with metastatic melanoma ranges from only 4.7 to 11 tumor that gives cancer a bad name” months, with a median survival of 8.5 months [8]. Melanoma is the deadliest form of skin cancer and 2.1. Melanoma is characterised by the dysfunction of one of the most aggressive of all neoplasms. The in- the epidermal melanin unit cidence of cutaneous melanoma has increased rapidly during the past several decades, and continues to do so Melanoma arises from the transformation of neu- at an alarming rate: The National Institutes of Health ral crest-derived melanocytes, the pigment cells of the predicts 62,480 new cases of melanoma in the year skin, which reside in the basal layer of the epidermis. 2009, with 8,420 of the patients succumbing to their dis- We now view melanoma as a complex tissue resulting ease [3]. The majority of these deaths are due to distant from disrupted skin homeostasis, rather than focusing metastases from the primary site because melanoma is on the melanoma cell, and the genes within it, alone. notorious for its propensity to metastasize. Although Normal skin homeostasis is maintained by dynamic in- localized melanoma is frequently curable by surgical teractions between the melanocytes and their microen- excision, metastatic melanoma is inherently resistant vironment, such as keratinocytes, fibroblasts, endothe- to most systemic treatments, and survival of patients lial and immunocompetent cells, and the extracellular with advanced disease has not improved in more than matrix. Similarly, during transformation and progres- 30 years [6,7]. Melanoma is poorly responsive to cyto- sion of melanocytes to melanoma cells, there are, how- toxic chemotherapy, and thus the survival of patients is ever deregulated, reciprocal and conspirational inter- based on screening, early detection, and wide resection actions between the neoplastic cells and the adjacent of the primary lesion. The overall survival for patients stromal cells [9,10]. T. Bogenrieder and M. Herlyn / The molecular pathology of cutaneous melanoma 269 Under normal physiological conditions,melanocytes sufficient phosphorylation of Rb, E2F is released and and keratinocytes form the ‘melanin unit’ in the epi- transactivates genes required for S phase entry, includ- dermis. In this unit, melanocytes and keratinocytes are ing cyclins E and A. CDK inhibitors (CKIs) serve as evenly aligned along the basement membrane zone at a negative regulators of the Rb pathway. CKIs are clas- ratio of 1:5–8. Each melanocyte extends with its den- sified into two distinct families on the basis of their drites into the upper layers of the epidermis, transfer- structural and functional characteristics. The mem- ring pigment-containing melanosomes to approximate- bers of the INK4 family of CKIs (p16Ink4a, p15Ink4b, ly 35 keratinocytes in its unit via dendritic process- p18Ink4c, and p19Ink4d) contain multiple ankyrin re- es. The melanin contained in these melanosomes ab- peats and act as negative regulators of CDK4/6 by bind- sorbs and scatters damaging ultraviolet radiation, there- ing to the catalytic subunit and preventing formation of by shielding the nucleic acids on the skin from damage the active cyclin-CDK complex. The Cip/Kip family of (reviewed in [9–12]). CKIs (p21Cip1/W af1, p27Kip1, and p57Kip2)ismore The undifferentiated keratinocytes of the basal lay- broadly acting and regulates both CDK4/6 and CDK2 er regulate melanocyte growth, number of dendrites activity. Each member of the family contains a char- and expression of cell surface molecules, providing ev- acteristic motif within the amino-terminal region that idence that this highly ordered organizational pattern enables them to bind to both cyclin and CDK subunits. serves as the structural basis for intercellular regulation. The stoichiometry between CDKs and CKIs is impor- Information is not yet available on how melanocytes tant and determines the activity of Rb and, ultimately, and keratinocytes can maintain this lifelong balance, the proliferative state of cells. which is only disturbed during transformation into a melanocytic nevus (‘mole’) or a melanoma. It is now 3.1. Alterations of the pRb pathway in melanoma generally accepted that melanoma risk is modulated by skin pigmentation patterns, such as those linked to The p16-cyclin D/Cdk4-pRb pathway is deregulated MC1R polymorphisms, and early exposure to ultravio-
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