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.

Chemokines, chemokine receptors and adhesion molecules on different human endothelia: discriminating the tissue-specific functions that affect leucocyte migration

“…Earlier work on endothelia had shown these cells to express CXCR1, 2, 3 and 4 but not b-chemokine receptors [22]. More recently CCR2, 3, 4 and 5 have also been identified [25,27,39]. Our studies agree broadly with the set of receptors identified by other researchers, although CCR2 was very low.…”

“…In vivo, it is more likely that secreted chemokines would be retained at the endothelial surface for some time and would then be released into the bloodstream. The functions of the endothelial chemokine receptors remain open [25,[37][38][39]42]. However, regardless of their function, this study shows that one phenotypic difference between endothelia lies in their profile of chemokine receptors.…”

“…Several studies have demonstrated different chemokine receptors on endothelia [19][20][21][22][23][24][25][26][27]. Because chemokine receptors may modulate chemokine expression by endothelium (by affecting chemokine transport, surface expression or reuptake), we determined whether the different endothelia express different chemokine receptors (Fig.…”

Monocyte chemoattractant protein‐1 is generated via TGF‐β by myofibroblasts in gastric intestinal metaplasia and carcinoma without H. pylori infection

“…However, based on several in vitro studies, the current belief is that MCP-1 does not promote proliferation or prosurvival characteristics in mammary tumor cells. (41) Monocyte chemoattractant protein-1 (MCP-1) is known as the most potent chemoattractant involved in macrophage migration. (42) One of the important roles of MCP-1 in tumor progression is through its involvement in macrophage recruitment relating to inflammation.…”

Proangiogenic effects of tumor cells on endothelial progenitor cells vary with tumor type in an in vitro and in vivo rat model

“…In response to the cytokines released by the tumor, EPCs are mobilized from bone marrow to the peripheral blood, home into the tumor site, differentiate into mature endothelial cells (ECs), and secrete angiogenic molecules to facilitate tumor vascularization (9,10). Numerous studies have demonstrated that several factors, such as VEGF, ABBREVIATIONS: 2D, 2-dimensional; 3D, 3-dimensional; CINC-2, cytokineinduced neutrophil chemoattractant 2; CM, conditioned medium; CT, computed tomography; EC, endothelial cell; EPC, endothelial progenitor cell; FCS, fetal calf serum; H&E, hematoxylin and eosin; MCP-1, monocyte chemoattractant protein 1; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PET, positron emission tomography; SP-MAP, shifted Poisson maximum a posteriori; TAM, tumor-associated macrophage; TRAIL, TNF-related apoptosis-inducing ligand macrophage inflammatory protein 2 (MIP-2), monocyte chemoattractant protein 1 (MCP-1), and TNF-related apoptosis-inducing ligand (TRAIL), play a crucial role in functional properties of ECs (10)(11)(12)(13)(14). The angiogenic switch, necessary for initiation of vessel formation, has long been identified to be orchestrated by the activity of angiogenic molecules (15).…”