title: Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression.
abstract: 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.
authors.affiliation: Laboratory of Molecular Immunoregulation, Laboratory of Experimental Immunology, Division of Basic Sciences; Intramural Research Support Program, SAIC, Frederick, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Salcedo
authors.forename: M L
authors.initials: ML
authors.lastname: Ponce
authors.forename: H A
authors.initials: HA
authors.lastname: Young
authors.forename: K
authors.initials: K
authors.lastname: Wasserman
authors.forename: J M
authors.initials: JM
authors.lastname: Ward
authors.forename: H K
authors.initials: HK
authors.lastname: Kleinman
authors.forename: J J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: W J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: 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
chemical_list: 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