The applicants have found that highly metastatic melanomas of C57BL/6 mice (BL6, JB/RH and JB/MS) do not express H-2Kb molecules and 1-galactosyl epitopes but express a common melanoma associated antigen (MAA) encoded by an ecotropic C-type retrovirus produced by these melanomas. It remains unknown why several independently arising melanomas manifest similar phenotypic properties. The finding of a novel melanoma-associated ecotropic retrovirus raises the question whether the retrovirus might play a role in melanoma formation or regulation of metastatic and phenotypic properties of melanoma cells. Our data showed that infection of cultured normal melanocytes from C57BL/6 and B10BR mice with ecotropic retrovirus derived from BL6 melanoma resulted in their malignant transformation. As a continuation of the previous investigations, they propose to explore the following working hypothesis: ecotropic retroviruses emerged in normal melanocytes might induce their malignant transformation by insertion into particular chromosomal locations, affecting the expression of some proto-oncogenes or tumor suppressor genes as well as genes controlling metastatic properties of melanoma cells. The major objectives of the proposed studies are to analyze the mechanism determining common phenotypic properties found in melanomas of C57BL/6 and to identify genes that are affected by insertional mutagenesis, that might play a role in melanoma formation and progression toward the metastatic phenotype. They will analyze the role of melanoma-associated ecotropic retroviruses in the pathogenesis of murine melanomas, by assessing their ability to induce melanomas or accelerate DMBA/croton oil induced melanoma formation. The metastatic properties of novel carcinogen-or retrovirus-induced melanomas as well as the mechanisms responsible for loss of H-2 class I molecules and alpha-galactosyl epitopes and TIMP-1 gene expression will be investigated. They will sequence the ecotropic retrovirus containing cosmid clones of the BL6 melanoma genomic library and identify genes affected by retrovirus insertion. Comparative analysis of expression of these genes in melanoma and normal melanocytes will be performed. This study might provide insights into the genetic basis of melanoma formation and metastatic progression.
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