Transforming growth factor-beta2 is a molecular determinant for site-specific melanoma metastasis in the brain

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-beta2 (TGF-beta2), an isoform of the TGF-beta family, as a molecular determinant of melanoma cell growth in the brain parenchyma. We found that the TGF-beta2 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-beta2 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-beta2 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-beta2 expression by murine melanoma cells is necessary for the establishment and growth of metastases in the brain parenchyma.