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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA059903-07
Application #
6172058
Study Section
Pathology B Study Section (PTHB)
Program Officer
Cole, John S
Project Start
1997-09-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
7
Fiscal Year
2000
Total Cost
$233,598
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Huang, Xiaojun; Raskovalova, Tatiana; Lokshin, Anna et al. (2005) Combined antiangiogenic and immune therapy of prostate cancer. Angiogenesis 8:13-23
Huang, Xiaojun; Wong, Michael K; Yi, Huiming et al. (2002) Combined therapy of local and metastatic 4T1 breast tumor in mice using SU6668, an inhibitor of angiogenic receptor tyrosine kinases, and the immunostimulator B7.2-IgG fusion protein. Cancer Res 62:5727-35
Zhu, Z; Sanchez-Sweatman, O; Huang, X et al. (2001) Anoikis and metastatic potential of cloudman S91 melanoma cells. Cancer Res 61:1707-16
Li, M; Xu, F; Muller, J et al. (1999) Loss of retrovirus production in JB/RH melanoma cells transfected with H-2Kb and TAP-1 genes. Virology 253:230-40
Li, M; Huang, X; Zhu, Z et al. (1999) Sequence and insertion sites of murine melanoma-associated retrovirus. J Virol 73:9178-86
Li, M; Xu, F; Muller, J et al. (1998) Ecotropic C-type retrovirus of B16 melanoma and malignant transformation of normal melanocytes. Int J Cancer 76:430-6
Xu, F; Carlos, T; Li, M et al. (1998) Inhibition of VLA-4 and up-regulation of TIMP-1 expression in B16BL6 melanoma cells transfected with MHC class I genes. Clin Exp Metastasis 16:358-70
Gorelik, E; Xu, F; Henion, T et al. (1997) Reduction of metastatic properties of BL6 melanoma cells expressing terminal fucose(alpha)1-2-galactose after alpha1,2-fucosyltransferase cDNA transfection. Cancer Res 57:332-6
Li, M; Muller, J; Rao, V et al. (1996) Loss of intracisternal A-type retroviral particles in BL6 melanoma cells transfected with MHC class I genes. J Gen Virol 77 ( Pt 11):2757-65
Muller, J; Khan, A S; Li, M et al. (1996) Phenotypic changes and loss of melanoma-specific endogenous C-type retroviruses in BL6 melanoma cells transfected with the H-2Kb gene. Melanoma Res 6:101-11

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