Abstract 2325: Thrombospondin 1 inhibits angiogenesis in liver metastases but not lung metastases due to differential cleavage activity of ADAMTS1

Abstract

Abstract Background: Metastases to any organ site require angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors including thrombospondin 1 (TSP1). The principal anti-angiogenic activity of TSP1 resides in a domain containing 3 TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. Methods and Results: Wild-type B16F10 melanoma cells formed increased liver metastases in Tsp1-null mice compared to controls but equivalent lung metastases in Tsp1-null mice and controls. Stable cell lines of B16F10, CT26 colon carcinoma, and RenCa renal carcinoma overexpressing full-length TSP1 or 3TSR were generated. Metastases from CT26 and RenCa cell lines over-expressing TSP1 were reduced in liver but not in lung. To determine why TSP1 blocked metastatic tumor growth in the liver but not the lung, we examined cleavage of recombinant TSP1 protein by liver and lung lysates and found that liver lysate cleaved TSP1 into its 3TSR domain much more efficiently that lung lysate. TSP1-mediated inhibition of CT26 lung metastases was restored when only the 3TSR domain was over-expressed rather than full-length TSP1. Liver lysate cleavage activity was significantly abrogated when ADAMTS1 activity was (1) neutralized using ADAMTS-1 antibody, (2) knocked down by lentiviral shRNA, or (3) absent in Adamts1-null liver lysate. Livers metastases generated from B16F10 cells over-expressing TSP1 in Adamts1-haploinsufficient mice demonstrated accelerated growth compared to growth in wild-type mice. Conclusions: TSP1 inhibits the growth of liver metastases but not lung metastases secondary to differential cleavage of TSP1 into anti-angiogenic fragments by ADAMTS1. This study emphasizes the importance of host organ environment in the regulation of tumor angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2325.