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Transforming Growth Factor-β2 Is a Molecular Determinant for Site-Specific Melanoma Metastasis in the Brain

Department of Cancer Biology, Cancer Metastasis Research Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Isaiah J. Fidler, Cancer Metastasis Research Center, The University of Texas M. D. Anderson Cancer Center, Unit 854, P. O. Box 301429, Houston, TX 77230-1429. Phone: 713-792-8580; Fax: 713-745-2174; E-mail: ifidler{at}mdanderson.org.

Key Words: TGF-β2 • melanoma • brain metastasis

Murine melanomas produce site-specific experimental brain metastases that reflect clinical reality. When injected into the internal carotid artery of mice, K-1735 melanoma cells produce metastatic lesions only in the brain parenchyma, whereas B16 melanoma cells and the somatic hybrid cells of B16 x K-1735 melanoma cells produce metastatic lesions only in the leptomeninges and ventricles. In the present study, we identified transforming growth factor-β2 (TGF-β2), an isoform of the TGF-β family, as a molecular determinant of melanoma cell growth in the brain parenchyma. We found that the TGF-β2 mRNA was highly expressed by the K-1735 cells, whereas the B16 cells or any B16 x K-1735 somatic cell-cell fusion hybrids have low expression. Transfection of the TGF-β2 gene into B16 cells resulted in the production of microscopic metastatic lesions in the brain parenchyma, without a decrease in metastasis to the leptomeninges or ventricles. TGF-β2 knockdown in the K-1735 melanoma cells significantly reduced metastasis to the brain parenchyma but did not induce metastasis to the leptomeninges or ventricles. These data show that TGF-β2 expression by murine melanoma cells is necessary for the establishment and growth of metastases in the brain parenchyma. [Cancer Res 2009;69(3):828–35]