Artigo Acesso aberto Revisado por pares

Animal Models of Melanoma

2005; Elsevier BV; Volume: 10; Issue: 2 Linguagem: Inglês

10.1111/j.1087-0024.2005.200409.x

ISSN

1529-1774

Autores

Linan Ha, Frances P. Noonan, Edward C. De Fabo, Glenn Merlino,

Tópico(s)

Computational Drug Discovery Methods

Resumo

hepatocyte growth factor/scatter factor ultraviolet Cutaneous melanoma is noteworthy for its therapeutic resistance, aggressive clinical behavior, and predisposition for late metastasis. In contrast to the declining incidence for many types of cancer, recent studies indicate that the incidence of melanoma has increased steadily in the last three decades (Howe et al., 2001Howe H.L. Wingo P.A. Thun M.J. Ries L.A. Rosenberg H.M. Feigal E.G. Edwards B.K. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends.J Natl Cancer Inst. 2001; 93: 824-842Crossref PubMed Scopus (644) Google Scholar), which demands an improved understanding of the molecular mechanisms involved in the genesis and progression of melanoma. Although a causal role for the ultraviolet (UV) portion of solar radiation in melanoma etiology is well accepted (Marks, 2000Marks R. Epidemiology of melanoma.Clin Exp Dermatol. 2000; 25: 459-463Crossref PubMed Scopus (241) Google Scholar), the functional relationship between genes and environmental sunlight in the pathogenesis of melanoma remains unclear. Basic melanoma research would benefit greatly from the availability of relevant animal models of melanoma, in which outstanding questions could be experimentally addressed. Unfortunately, investigations into the initiation and progression of melanoma have been hampered by the paucity of such animal models. An "ideal" animal model would accurately recapitulate human disease, particularly the UV-based etiology, the molecular genetics, and the histopathological architecture of cutaneous melanoma. Furthermore, it should be amenable to genetic and immunologic manipulation. Although a number of animal melanoma models have been described (reviewed inJhappan et al., 2003Jhappan C. Noonan F.P. Merlino G. Ultraviolet radiation, and cutaneous malignant melanoma.Oncogene. 2003; 22: 3099-3112Crossref PubMed Scopus (191) Google Scholar), which will briefly be recapitulated here, the histopathological appearance and graded progression of the arising melanocytic malignancies have been, for the most part, distinct from human cutaneous melanoma. Large animal models of melanoma have been reported, which include Sinclair swine and Camargue horse (Fleury et al., 2000Fleury C. Berard F. Balme B. Thomas L. The study of cutaneous melanomas in Camargue-type gray-skinned horses (1): Clinical–pathological characterization.Pig Cell Res. 2000; 13: 39-46Crossref PubMed Scopus (55) Google Scholar); however, neither develops melanomas with a sunlight-based etiology. The non-mammalian Xiphophorus fish model has been used to study the photobiology and genetics of melanoma. Although the Xiphophorus fish develops melanomas spontaneously and is also responsive to UV radiation (Walter and Kazianis, 2001Walter R.B. Kazianis S. Xiphophorus interspecies hybrids as genetic models of induced neoplasia.Ilar J. 2001; 42: 299-321Crossref PubMed Scopus (101) Google Scholar), the tumor histology differs substantially from human melanomas. The opossum Monodelphis domestica is an interesting model that also responds to UV to initiate melanoma (Kusewitt et al., 1991Kusewitt D.F. Applegate L.A. Ley R.D. Ultraviolet radiation-induced skin tumors in a South American opossum (Monodelphis domestica).Vet Path. 1991; 28: 55-65Crossref PubMed Scopus (52) Google Scholar). But the inability to derive inbred opossums ultimately limits the utility of this model for genetic and immunologic investigations. Melanomas have been reported in several guinea-pig models and in the Syrian hamster; however, the tumors were initiated by exposure to the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) (reviewed inBardeesy et al., 2000Bardeesy N. Wong K.K. DePinho R.A. Chin L. Animal models of melanoma: Recent advances and future prospects.Adv Cancer Res. 2000; 79: 123-156Crossref PubMed Google Scholar) an agent of unknown etiological relevance, and not by UV alone. Mice in general represent an outstanding animal model, due in large part to the extensive understanding of mouse genetics; unfortunately, melanomas are extremely difficult to initiate in mice. Moreover, like other animal models, melanomas that do arise are typically dermal in origin, and thus do not show histopathologic similarities to human disease. The dermal origin of mammalian melanomas is likely a consequence of the normal location of melanocytes within the skin. In most mammals, including mice, melanocytes are confined to the hair follicles within the dermis. In contrast, melanocytes in human skin reside in the basal layer of the epidermis. A number of mouse models of cutaneous melanoma have now been generated (reviewed inBardeesy et al., 2000Bardeesy N. Wong K.K. DePinho R.A. Chin L. Animal models of melanoma: Recent advances and future prospects.Adv Cancer Res. 2000; 79: 123-156Crossref PubMed Google Scholar;Merlino and Noonan, 2003Merlino G. Noonan F.P. Modeling gene–environment interactions in malignant melanoma.Trends Mol Med. 2003; 9: 102-108Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). The model that has been most thoroughly analyzed at the molecular level arises because of expression of activated Ras and inactivation of the ink4a/arf locus (Chin et al., 1999Chin L. Tam A. Pomerantz J. Essential role for oncogenic Ras in tumour maintenance.Nature. 1999; 400: 468-472Crossref PubMed Scopus (735) Google Scholar), already implicated as encoding a melanoma tumor suppressor. Recently, we have derived a melanoma model in neonatally UV-irradiated mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) (Takayama et al., 1996Takayama H. La Rochelle W.J. Anver M. Bockman D.E. Merlino G. Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development.Proc Natl Acad Sci USA. 1996; 93: 5866-5871Crossref PubMed Scopus (173) Google Scholar;Noonan et al., 2001Noonan F.P. Recio J.A. Takayama H. Neonatal sunburn and melanoma in mice.Nature. 2001; 413: 271-272Crossref PubMed Scopus (301) Google Scholar). HGF/SF is a multifunctional cytokine that can elicit mitogenic, motogenic, and/or morphogenic responses in a variety of cells, including melanocytes, that express its receptor tyrosine kinase c-Met. The c-Met receptor is highly expressed in many mouse and human tumors and has been implicated in oncogenesis (Jeffers et al., 1996Jeffers M. Rong S. Vande Woude G.F. Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis.J Mol Med. 1996; 74: 505-513Crossref PubMed Scopus (260) Google Scholar;Danilkovitch-Miagkova and Zbar, 2002Danilkovitch-Miagkova A. Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors.J Clin Invest. 2002; 109: 863-867Crossref PubMed Scopus (258) Google Scholar). A key feature of the HGF/SF-transgenic mouse is the ectopic localization of HGF/SF-expressing melanocytes to the epidermis, upper regions of the dermis, and at the epidermal–dermal junction, phenotypically more akin to human skin (Noonan et al., 2001Noonan F.P. Recio J.A. Takayama H. Neonatal sunburn and melanoma in mice.Nature. 2001; 413: 271-272Crossref PubMed Scopus (301) Google Scholar;Recio et al., 2002Recio J.A. Noonan F.P. Takayama H. Ink4a/arf deficiency promotes ultraviolet radiation-induced melanoma genesis.Cancer Res. 2002; 62: 6724-6730PubMed Google Scholar). Cutaneous melanomas then arise in the UV-irradiated HGF/SF-transgenic mouse in distinct stages that resemble human disease, including grossly identifiable premalignant lesions, intermediate radial and vertical growth stages of heterogeneous histopathologies, and late metastatic spread to a variety of distant organs Figure 1 (Noonan et al., 2001Noonan F.P. Recio J.A. Takayama H. Neonatal sunburn and melanoma in mice.Nature. 2001; 413: 271-272Crossref PubMed Scopus (301) Google Scholar;Recio et al., 2002Recio J.A. Noonan F.P. Takayama H. Ink4a/arf deficiency promotes ultraviolet radiation-induced melanoma genesis.Cancer Res. 2002; 62: 6724-6730PubMed Google Scholar). A single neonatal dose of mild erythemal (skin reddening) UV radiation was necessary and sufficient to induce melanoma in the HGF/SF-transgenic mouse with relatively high penetrance, arising with histopathologic and molecular pathogenetic profiles reminiscent of human melanoma (Noonan et al., 2001Noonan F.P. Recio J.A. Takayama H. Neonatal sunburn and melanoma in mice.Nature. 2001; 413: 271-272Crossref PubMed Scopus (301) Google Scholar). These data experimentally support the hypothesis based on long-debated epidemiological evidence that childhood sunburn is in fact a high melanoma risk factor (Whiteman et al., 2001Whiteman D.C. Whiteman C.A. Green A.C. Childhood sun exposure as a risk factor for melanoma: A systematic review of epidemiologic studies.Cancer Causes Cont. 2001; 12: 69-82Crossref PubMed Scopus (480) Google Scholar). When placed on a background devoid of Ink4a/Arf, the median time to melanoma development induced by UV irradiation of HGF/SF-transgenic mice was significantly reduced (Recio et al., 2002Recio J.A. Noonan F.P. Takayama H. Ink4a/arf deficiency promotes ultraviolet radiation-induced melanoma genesis.Cancer Res. 2002; 62: 6724-6730PubMed Google Scholar), demonstrating that ink4a/arf plays a critical role in UV-induced melanoma development and strongly suggesting that sunburn is a significant risk factor in human kindreds harboring germ-line mutations in INK4a/ARF (Bishop et al., 2002Bishop D.T. Demenais F. Goldstein A.M. Melanoma Genetics Consortium. Geographical variation in the penetrance of CDKN2A mutations for melanoma.J Natl Cancer Inst. 2002; 94: 894-903Crossref PubMed Scopus (394) Google Scholar). Taken together, our data show that the HGF/SF-transgenic mouse represents an authentic animal model for human cutaneous melanoma. Although UV exposure is strongly implicated in the etiology of cutaneous melanoma, there are conflicting opinions on the roles of UVB and UVA, which differ in their ability to initiate DNA damage, stimulate cell-signaling pathways, and induce immune alterations. To address this issue, HGF/SF-transgenic mice were exposed as neonates to light from specialized optical sources, emitting isolated or combined UVB or UVA wavebands or solar-simulating radiation (De Fabo et al., 2004De Fabo E.C. Noonan F.P. Fears T. Merlino G. Ultraviolet B, but not ultraviolet A radiation initiates melanoma.Cancer Res. 2004; 64: 6372-6376Crossref PubMed Scopus (197) Google Scholar) Figure 2. All UVB-containing light sources were found to effectively initiate melanoma. In sharp contrast, the response of transgenic mice irradiated with either isolated UVA, or a sunlamp filtered to remove the UVB, was the same as unirradiated animals. These data show that in this albino mouse model UVB is responsible for the induction of melanoma, whereas UVA is ineffective even at doses considered physiologically relevant. Data from this animal model may be relevant with respect to risk assessment from exposure to both solar and artificial UVB, and may facilitate the development of more efficacious sun protection strategies. In summary, the HGF/SF-transgenic mouse appears to represent a useful surrogate for human melanoma. This animal model should permit a relevant assessment of both the genetic basis for the pathogenesis and progression of melanoma in different in vivo stages and the risk associated with exposure to various candidate etiological agents and conditions. It is anticipated that identification of novel factors and/or pathways in melanoma genesis through use of this animal model will provide insight into mechanisms underlying cutaneous melanoma, as well as new avenues for more effective treatment.

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