Thrombospondin-1: the paradigm of antiangiogenic agents endowed with multiple mechanisms of action

Uncontrolled neovascularization occurs in several angiogenesis-dependent
diseases, including cancer. Neovascularization is tightly controlled by the balance between
angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis
inhibitors identified so far affect neovascularization by different mechanisms of action.
Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful
endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic
growth factors and effectors in the extracellular environment, and directly, by inducing an
antiangiogenic program in endothelial cells following engagement of specific receptors
including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In
view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of
antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics,
gene therapy strategies, and agents that up-regulate TSP-1 expression. This review
discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and
therapeutic potential, drawing our experience with angiogenic growth factor-interacting
TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic
agents.