Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression
Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression
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DOI：
10.1182/blood.v96.1.34.013a49_34_40
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发表时间：
2000-07-01
期刊：
影响因子：
20.3
通讯作者：
Murphy, WJ
中科院分区：
文献类型：
--
作者：
Salcedo, R;Ponce, ML;Murphy, WJ
虽然几种CXC趋化因子已显示诱导血管生成并在肿瘤生长中发挥作用，但迄今为止，没有报道CC趋化因子家族的成员在血管生成中发挥直接作用。在这里，我们报告CC趋化因子，单核细胞趋化蛋白1（MCP-1），诱导人内皮细胞在纳摩尔浓度的趋化性。这种趋化反应被MCP-1的单克隆抗体所抑制，MCP-1还通过鸡胚绒毛尿囊膜和基质胶塞试验在体内诱导血管形成。正如预期的那样，MCP-1诱导的血管生成反应伴随着炎症反应。在没有白细胞浸润的情况下使用大鼠主动脉发芽试验，我们排除了MCP-1的血管生成作用依赖于白细胞产物的可能性。此外，MCP-1对血管生成的直接作用与MCP-1受体CCR 2在内皮细胞上的表达一致。对来自人乳腺癌细胞系的上清液的评估证实了MCP-1的产生。用MCP-1的中和抗体治疗携带人乳腺癌细胞的免疫缺陷小鼠，导致存活率显著增加，并抑制肺微转移的生长。综上所述，我们的数据表明MCP-1可以作为血管生成的直接介质，作为由一些肿瘤大量产生的趋化因子，它也可以直接促进肿瘤的进展。因此，采用MCP-1拮抗剂与其他血管生成抑制剂组合的治疗可以实现对肿瘤生长的更全面的抑制。（血。2000;96：34-40）（C）2000年由美国血液学会。
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. (Blood. 2000;96:34-40) (C) 2000 by The American Society of Hematology.