title: Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC).
abstract: Angiogenesis is essential for tumor growth and metastasis. VEGF has been shown to be a central player in this process. The biological activity of VEGF is mainly mediated by two tyrosine kinase receptors, VEGFR-1 and VEGFR-2. While increasing evidence suggests that VEGF/VEGFR-1 signaling is crucial for tumor angiogenesis, its molecular mechanism is not well understood. Here we show that VEGFR-1 knockdown dramatically inhibits tumor growth. This inhibition is associated with significant decrease of tumor VEGF levels and tumor angiogenesis as well as an increased tumor necrosis. Moreover, we demonstrate that VEGF in CRCC tumors is mainly produced by tumor stromal cells instead of the tumor cells themselves. It has been shown that macrophages constitute a significant part of tumor stromal cells and produce a large amount of VEGF. We therefore examined the macrophage infiltration in the xenograft tumors. Remarkably, VEGFR-1 knockdown attenuates the tumor macrophages infiltration. To understand the mechanism, we investigated the impact of VEGFR-1 knockdown on the expression of monocyte chemoattractant protein-1 (MCP-1), one of the main chemoattractants for macrophages. Significantly, VEGFR-1 knockdown inhibits MCP-1 expression of CRCC cells. Taken together, these data indicate that VEGF/VEGFR-1 signaling plays an essential role in initiating tumor angiogenesis by regulating MCP-1 expression, which in turn, attracts macrophages infiltration and VEGF production. Thus, these studies suggest that blockade of VEGFR-1 function may provide a tumor-specific, VEGF-based therapeutic strategy for treatment of CRCC.
authors: Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors: Chenghai
authors: C
authors: Li
authors: Bin
authors: B
authors: Liu
authors: Zonghan
authors: Z
authors: Dai
authors: Yunxia
authors: Y
authors: Tao
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000628:therapy*; D008264:Macrophages / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; D042442:Vascular Endothelial Growth Factors; D040281:Vascular Endothelial Growth Factor Receptor-1; D020780:Matrix Metalloproteinase 9