MARIETTA BIOL 309 - Molecular Biology of Human Melanoma Development and Progression

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ETIOLOGYCLINICAL AND PATHOLOGIC EVIDENCE OF TUMOR PROGRESSIONIN VITRO GROWTH REQUIREMENTSEXPERIMENTAL TUMOR DEVELOPMENT AND PROGRESSIONMELANOMA-ASSOCIATED ANTIGENSMARKERS DISTINGUISHING CELLS FROM DIFFERENT STAGES OF MELANOMA PROGRESSIONMELANOMA BIOLOGY AND TREATMENTMOLECULAR BIOLOGY AND DETECTION OF OCCULT DISEASEACKNOWLEDGMENTSREFERENCES132 SAUTER AND HERLYN MOLECULAR CARCINOGENESIS 23:132–143 (1998)© 1998 WILEY-LISS, INC.Molecular Biology of Human Melanoma Developmentand ProgressionEdward R. Sauter and Meenhard Herlyn*The Wistar Institute, Philadelphia, PennsylvaniaIn the United States, Australia, Northern Europe, and Canada, malignant melanoma is increasing at a fasterrate than any other cancer, with the exception of lung cancer in women. Major advances have been made inthe molecular biology and immunology of melanoma. These advances in basic science have led to more ratio-nal approaches to specifically targeting melanoma cells, with promising results in the clinic. An increasedunderstanding of how melanoma spreads has led to more selective, less invasive surgical procedures that donot compromise patient health. Combinations of chemotherapy and immunotherapy are now available forpatients with advanced melanoma that affect both the length and quality of the patients’ lives. This review ofthe molecular biology of melanoma development and progression discusses the disease’s etiology, moleculargenetics, cell-surface antigens, experimental models, biological markers, and new forms of treatment. As wecontinue to learn more about malignant melanoma, we will be able to devise more specific and effectivetreatments that will give patients with this potentially deadly disease longer and more productive lives. Mol.Carcinog. 23:132–143, 1998.© 1998 Wiley-Liss, Inc.Key words: melanoma; tumor markers; treatmentETIOLOGYThe incidence of melanoma is increasing dramati-cally in the developed world [1], having nearlydoubled between 1980 and 1990. While the etiologicfactors leading to melanoma are unknown, three fac-tors should be considered. First, Caucasians have atenfold higher risk of melanoma on sun-exposed ar-eas than blacks do [2]. Second, epidemiologic studiespoint to a role for sunlight in the development ofmelanoma [1]. Third, hereditary melanoma exists andaccounts for 5–10% of all melanoma cases [3]. Manypatients with hereditary melanoma have multiple nevi,and patients with many nevi have a greater risk ofmelanoma than those with few nevi [4].Ultraviolet LightThe ultraviolet light (UV) present in sunlight, es-pecially UV within the B spectrum (290–320 nmwavelength), has been implicated as a possible causeof melanoma development. UV has been found toincrease DNA instability [5], inhibit antioxidants [6],and suppress the immune system [7]. Intermittentintense exposure to sunlight during childhood leadsto a significantly higher incidence of melanoma inadults [8].UV induces the expression of transforming growthfactor (TGF)-α [9] and nerve growth factor [10] onmelanocytes. N-ras mutations are frequently ob-served opposite pyrimidine dimers [11], a knownconsequence of UV damage. We recently identifieda human melanoma in a neonatal foreskin xenograftgrafted to an immunodeficient mouse whose skinwas treated with a single dose of 7,12-dimethyl-benz[a]anthracene (DMBA) followed by chronic UVexposure.In three experimental animal systems, UV eithercauses or contributes to melanoma development. TheSouth American opossum Monodelphis domestica,which lacks a DNA repair mechanism, develops mela-nomas at a high rate after approximately 1 yr of UVexposure [12]. Administration of DMBA followed bycroton oil with UV leads to melanoma in mouse skin[13]. Crosses between platyfish and swordtail fishproduce offspring that after chronic UVB exposuredevelop melanomas [14].Molecular GeneticsKaryotype analysis of dysplastic nevi and melano-mas demonstrates nonrandom changes in chromo-somes 1, 6, 7, 9, and 10. Nonrandom karyotypic*Correspondence to: The Wistar Institute, 3601 Spruce Street,Philadelphia, PA 19104.Received 11 February 1998; Accepted 9 April 1998Abbreviations: UV, ultraviolet light; TGF, transforming growth fac-tor; DMBA, 7,12-dimethylbenz[a]anthracene; IFN, interferon; EGFR,epidermal growth factor receptor; CDK, cyclin-dependent kinase; RGP,radial growth phase; VGP, vertical growth phase; TPA, 12-O-tetradecanoylphorbol-13-acetate; bFGF, basic fibroblast growth fac-tor; CAM, cell adhesion molecule; HOX, homeobox containing gene;IL, interleukin; SV40, simian virus 40; CAM, cell adhesion molecule;ICAM-1, intercellular CAM-1; N-CAM, neural CAM; PDGF, platelet-derived growth factor; IGF-I, insulin-like growth factor-1; MSH, mel-anocyte-stimulating hormone; VEGF, vascular endothelial growthfactor; HMW-MAA, high molecular weight melanoma-associated an-tigen; MAGE, melanoma antigen genes; RT-PCR, reverse transcrip-tion–polymerase chain reaction.REVIEWSMELANOMA 133changes in chromosome 1 were observed in 53 of 58advanced melanomas [15]. In most cases, the abnor-mality was a deletion or translocation of 1p12-22.Bale et al. [16] identified 1p36 as a frequently alteredregion. Trent et al. [17] identified nonrandom dele-tions in chromosome 6 in melanoma cell lines, andloss of heterozygosity was found on 6q in melanomametastases [18]. Melanoma in the platyfish andswordfish suggests that the tumor suppressor geneTu, which maps to 7p11-13 in humans, is respon-sible for the tumor phenotype [19]. Alterations onchromosome 9 include a 2–3 Mb deletion proximalto the interferon (IFN)-α gene cluster in 85% of mela-noma tumor and cell line DNAs [20]. This region con-tains the tumor suppressor gene p16. Multiplealterations on chromosome 10q have been associatedwith the early stages of melanocytic neoplasia [21].Oncogenes and Suppressor GenesrasExpression of all three ras genes (N-ras, Ha-ras, andKi-ras) has been detected in human melanomas. Ofthe three genes, N-ras appears to be the most com-monly mutated, with up to 60% of primary melano-mas containing mutated N-ras [22]. N-ras mutationsare most often found in melanoma samples from sun-exposed areas of the body, suggesting an associationbetween UV and these alterations.c-mycMelanoma cell lines frequently demonstrateoverexpression of c-myc [23], but in vitro effects can-not be excluded. Increased c-myc expression is gen-erally associated with tumorigenicity parameters suchas anchorage-independent growth in soft agar andtransformation of NIH/3T3


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