Thrombospondins: Endogenous inhibitors of angiogenesis

Abstract

The thrombospondin (TSP) gene family consists of five members, two of which, TSP1 and TSP2, have been shown to play important roles in the regulation of angiogenesis. While TSP1 and TSP2 are secreted into the extracellular environment, they do not play structural roles but rather function to regulate cellular behavior by interaction with numerous cell-surface receptors, proteases, cytokines, and other bioactive proteins. As a consequence, these TSPs are termed matricellular proteins. TSP1, but not TSP2, is capable of activating latent TGFβ, and can thereby stimulate the production of extracellular matrix. Matricellular TSPs inhibit angiogenesis both by causing apoptosis of endothelial cells (EC) and by inhibiting their proliferation. However, under some circumstances TSP1 has also been shown to be proangiogenic. TSPs interact with matrix metalloproteinases (MMPs) 2 and 9 and function as clearance factors by directing these MMPs to the scavenger receptor, LRP1, and thence to lysosomal degradation. As a consequence, TSPs function to regulate cell adhesion. TSP1 also inhibits nitric oxide-stimulation of EC proliferation by interaction with the CD47/integrin-associated protein receptor. Finally, by virtue of their ability to inhibit angiogenesis, TSPs have the potential to inhibit tumor growth and metastases, a property that may have clinical applications. © 2008 Springer US.