The role of thrombospondin-1 in tumor progression.
The role of thrombospondin-1 (TSP-1) in tumor progression is both complex and controversial. It is clear from the literature that the function of TSP-1 in malignancy depends on the presence of other factors and the level of TSP-1 expression in the tumor tissue. High levels of TSP-1 secreted by tumors, which were engineered to overexpress TSP-1, inhibit tumor growth, while anti-sense inhibition of TSP-1 production in certain tumors also inhibits growth. Clearly, the presence of other factors in these experimental systems must be important. The role of TSP-1 in angiogenesis also depends on the levels of TSP-1, the presence and level of angiogenic stimulators such as basic fibroblast growth factor (bFGF), and the localization of TSP-1 in the tissue. Matrix-bound TSP-1 promotes capillary tube formation in the rat aorta model of angiogenesis, while TSP-1 inhibits bFGF- induced angiogenesis in the rat cornea model. The inhibitory effect also depends on the proteolytic state of TSP-1 since the amino terminus promotes angiogenesis in the cornea model, while the remaining 140-kDa fragment inhibits bFGF-induced angiogenesis. Both the stimulatory and inhibitory effects of TSP-1 are likely due to upregulation of matrix-degrading enzymes and their inhibitors. These enzymes are critical for maintaining optimal matrix turnover during angiogenesis. These varied TSP-1-dependent mechanisms offer new targets for the development of anti-angiogenic therapeutics for the treatment of a variety of cancers, as well as other pathologies involving inappropriate angiogenesis such as diabetic retinopathy.
Sargiannidou
I
I
Department of Pathology and Laboratory Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania 19102, USA.
Zhou
J
J
Tuszynski
G P
GP
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1