Regulation of tumor growth and metastasis by thrombospondin-1

Thrombospondin-1 (TSP1) is an extracellular matrix glycoprotein that influences cell adhesion, motility, and growth, Based on its effects on tumor and endothelial cell behavior, this member of the thrombospondin gene family has attracted interest as a potential regulator of tumor growth and metastasis, Initial studies have confirmed that increased TSP1 expression suppresses growth or metastasis of some tumors in vivo and inhibits angiogenesis. These activities are cell. type specific, however, since overexpression of TSP1 in some tumors causes increased tumor progression. One basis for these apparently conflicting observations may be the complexity of the protein, TSP1 interacts specifically with several cell-surface receptors, heparan sulfate proteoglycans, growth factors, and other matrix components. These multiple binding specificities, combined with the ability of TSP1 to activate latent transforming growth factor beta and inhibit several proteases, suggest; that exposure to TSP1 may initiate several intracellular signals, The integration of these signals may allow varied responses to TSP1, Furthermore, these signals may be received by the tumor cells, endothelial cells responsible for neovascularization, stromal cells, or cells of the host immune system, TSP1 influences specific behaviors of each cell type. Relating these phenomena to the molecular interactions of TSP1 observed in vitro may lead to novel therapeutic strategies for controlling cancer progression and metastasis.