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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 34-40
Human endothelial cells express CCR2 and respond to MCP-1:
direct role of MCP-1 in angiogenesis and tumor progression
Rosalba Salcedo,
Maria Lourdes Ponce,
Howard A. Young,
Ken Wasserman,
Jerrold M. Ward,
Hynda
K. Kleinman,
Joost J. Oppenheim, and
William J. Murphy
From the Laboratory of Molecular Immunoregulation, Laboratory of
Experimental Immunology, Division of Basic Sciences; Intramural
Research Support Program, SAIC; Veterinary and Tumor Pathology Section,
Office of Laboratory Animal Resources, Frederick Cancer Research and
Development Center, Frederick, MD; and Cell Biology Section, National
Institute of Dental and Craniofacial Research, Bethesda, MD.
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 has been reported to play a direct role in
angiogenesis. Here we report that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), induced chemotaxis of human endothelial cells at nanomolar concentrations. This chemotactic
response was inhibited by a monoclonal antibody to MCP-1. MCP-1 also
induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic 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 infiltrates, we ruled out the possibility that the
angiogenic effect of MCP-1 depended on leukocyte products. Moreover,
the direct effect of MCP-1 on angiogenesis was consistent with the
expression of CCR2, the receptor for MCP-1, on endothelial cells.
Assessment of supernatant from a human breast carcinoma cell line
demonstrated the production of MCP-1. Treatment of immunodeficient mice
bearing human breast carcinoma cells with a neutralizing antibody 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 tumor progression. Therefore, therapy employing
antagonists of MCP-1 in combination with other inhibitors of
angiogenesis may achieve more comprehensive inhibition of tumor growth.
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