Tumor progression: the effects of thrombospondin-1 and -2.
The thrombospondins (TSPs) are a family of proteins that regulate tissue genesis and remodeling. In many tumors, down-regulation of TSPs accompanies activation of oncogenes or inactivation of tumor suppresser genes and appears to be a prerequisite for the aquisition of a pro-angiogenic phenotype. The normal suppression of angiogenesis by TSP-1 and -2 involves multiple mechanisms including direct interaction with vascular endothelial cell growth factor (VEGF), inhibition of matrix metalloproteinase 9 (MMP9) activation, inhibition of endothelial cell migration and induction of endothelial cell apoptosis. The importance of down-regulation of TSPs for tumor progression is further established by the fact that several different approaches that are designed to increase the levels of TSP-1 or -2 in tumor tissue inhibit tumor growth. These approaches include cell-based gene therapy, low dose chemotherapeutics and systemic delivery of recombinant proteins or synthetic peptides that include type 1 repeat (TSR) sequences. Initial studies indicate that these reagents, in combination with established approaches for the treatment of cancer, will offer more efficacious therapies.
Lawler
Jack
J
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA. jlawler@bidmc.harvard.edu
Detmar
Michael
M
D015536:Down-Regulation; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D000099262:Thrombospondin 2
D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2