Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression

Although several CXC chemokines have been shown to induce angiogenesis and play roles in tumor growth, to date, no member of the CC chemokine family h as been reported to play a direct role in angiogenesis. Here we report that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), induced chemotax is of human endothelial cells at nanomolar concentrations. This chemotactic response was inhibited by a monoclonal antibody to MCP-1, MCP-1 also induc ed the formation of blood vessels in vivo as assessed by the chick chorioal lantoic membrane and the matrigel plug assays. As expected, the angiogenic response induced by MCP-1 was accompanied by an inflammatory response. With the use of a rat aortic sprouting assay in the absence of leukocytic infil trates, we ruled out the possibility that the angiogenic effect of MCP-1 de pended on leukocyte products. Moreover, the direct effect of MCP-1 on angio genesis was consistent with the expression of CCR2, the receptor for MCP-1, on endothelial cells. Assessment of supernatant from a human breast carcin oma cell line demonstrated the production of MCP-1. Treatment of immunodefi cient mice bearing human breast carcinoma cells with a neutralizing antibod y to MCP-1 resulted in significant increases in survival and inhibition of the growth of lung micrometastases. Taken together, our data indicate that MCP-1 can act as a direct mediator of angiogenesis, As a chemokine that is abundantly produced by some tumors, it can also directly contribute to tumo r progression. Therefore, therapy employing antagonists of MCP-1 in combina tion with other inhibitors of angiogenesis may achieve more comprehensive i nhibition of tumor growth. (Blood. 2000;96:34-40) (C) 2000 by The American Society of Hematology.