Extracellular matrix protein βig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation

Metastasis, the major cause of cancer death, is a multistep process that requires 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 a considerable impact on the metastatic process during tumorigenesis. Here we report that elevated expression of βig-h3/TGFBI (transforming growth factor, β-induced), an extracellular matrix protein secreted by colon cancer cells, is associated with high-grade human colon cancers. Ectopic expression of the βig-h3 protein enhanced the aggressiveness and altered the metastatic properties of colon cancer cells in vivo. Inhibition of βig-h3 expression dramatically reduced metastasis. Mechanistically, βig-h3 appears to promote 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 α_vβ₅-Src signaling pathway. Thus, cancers associated with overexpression of βig-h3 may have an increased metastatic potential, leading to poor prognosis in cancer patients.