Abstract
Tumors implanted near the scapulae have been shown to grow four times faster than the same tumors implanted at the iliac crest. Although there were marked differences in the vascularization of tumors from these two different sites, the mechanism controlling regional angiogenesis was not identified. Here, we show site-specific growth of intraperitoneal tumor implants in the mouse abdomen. Our data indicate that the angiogenic response of the host differs significantly between the upper and lower sites in the mouse abdomen and reveal that the expansion of tumor mass is restricted to sites with low angiogenic responses, such as the bowel mesentery in the lower abdomen. We show that, in this model, this suppression of angiogenesis is due to an expression gradient of thrombospondin-1 (TSP-1), a potent endogenous angiogenesis inhibitor. Mice with a targeted deletion of TSP-1 no longer show regional restriction of tumor growth. The physiologic relevance of these findings may be seen in patients with peritoneal carcinomatosis, whereby tumors spread within the peritoneal cavity and show differential growth in the upper and lower abdomen. We hypothesize that the difference in tumor growth in these patients may be due to a gradient of TSP-1 expression in stroma. Finally, our studies suggest that upregulation of TSP-1 in tumor cells is one method to suppress the growth of tumors in the upper abdomen.