| Metastasis, the major cause of cancer death, is a multi-step process that requires the interactions between cancer cells and stromal cells, and between cancer cells and extracellular matrix. Molecular alterations of the extracellular matrix in the tumor microenvironment have considerable impact on the metastatic process during tumorigenesis. Aberrant expression of betaig-h3/TGFBI (Transforming growth factor, beta-induced), an extracellular matrix protein, was found in colorectal tumors by SAGE and gene microarray analysis. Here we report that overexpression of betaig-h3/TGFBI in the SW480 colon cancer cell line enhanced the aggressiveness and altered the metastatic properties of the cells in vivo. Inhibiting betaig-h3/TGFBI expression in an aggressive isogenic colon cancer cell line SW620 dramatically reduced metastasis. Mechanistically, betaig-h3/TGFBI appears to promote cell extravasation, a critical step in the metastatic dissemination of cancer cells, by inducing the dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin &agr;vbeta5-Src signaling pathway. Thus, cancers associated with overexpression of betaig-h3/TGFBI may have an increased metastatic potential leading to poor prognosis in cancer patients. |
