DF/HCC Program Affiliation

Angiogenesis, Invasion, and Metastasis, Co-Leader

Research Abstract

Thrombospondin-1 (TSP-1) and -2 are extracellular, calcium-binding proteins that regulate cellular phenotype by orchestrating the assembly of multiprotein complexes on the cell surface. These complexes include CD36, transforming growth factor beta, proteoglycans, integrins and integrin associated proteins. Thrombospondin-1 on the cell surface inhibits (1) proliferation of endothelial cells and tumor cells in vitro, (2) endothelial cell migration and angiogenesis, and (3) the growth of experimental and naturally occurring tumors in vivo. To establish a role for TSP-1 in the progression of spontaneously occurring tumors that arise at orthotopic sites in vivo, we have crossed mice that are deficient in TSP-1 with mice that are deficient in p53. Mice that lack TSP-1 exhibit decreased survival and altered tumor specturm. Consistent with these observations, overexpression of TSP-1 inhibits tumor growth and angiogenesis. In addition, systemic injection of recombinent type 1 repeats of TSP-1 inhibits the growth of tumors formed from the subcutaneous injection of B16F10 melanoma cells. These data indicate that tumor growth is inversely proportional to TSP-1 protein expression and that down-regulation of TSP-1 is involved in tumor progression.

Publications

• Yee KO, Streit M, Hawighorst T, Detmar M, Lawler J.Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta.Am J Pathol 2004 Aug;165(2):541-52.
  15277228
• Lawler J, Detmar M.Tumor progression: the effects of thrombospondin-1 and -2.Int J Biochem Cell Biol 2004 Jun;36(6):1038-45.
  15094119
• Tan K, Duquette M, Liu JH, Dong Y, Zhang R, Joachimiak A, Lawler J, Wang JH.Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implication.J Cell Biol 2002 Oct 28;159(2):373-82.
  12391027
• Miao WM, Seng WL, Duquette M, Lawler P, Laus C, Lawler J.Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms.Cancer Res 2001 Nov 1;61(21):7830-9.
  11691800
• Miao WM, Vasile E, Lane WS, Lawler J.CD36 associates with CD9 and integrins on human blood platelets.Blood 2001 Mar 15;97(6):1689-96.
  11238109