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 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.
Salcedo
R
R
Laboratory of Molecular Immunoregulation, Laboratory of Experimental Immunology, Division of Basic Sciences; Intramural Research Support Program, SAIC, Frederick, MD, USA.
Ponce
M L
ML
Young
H A
HA
Wasserman
K
K
Ward
J M
JM
Kleinman
H K
HK
Oppenheim
J J
JJ
Murphy
W J
WJ
D000482:Allantois / Q000098:blood supply; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005109:Extracellular Matrix; D005260:Female; D006801:Humans; D007797:Laminin; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011509:Proteoglycans; D051381:Rats; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C059485:matrigel; D003094:Collagen