Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice
Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice
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DOI：
10.1158/0008-5472.can-07-6705
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Brekken, Rolf A.
中科院分区：
文献类型：
--
作者：
Dineen, Sean P.;Lynn, Kristi D.;Brekken, Rolf A.
巨噬细胞是肿瘤微环境中丰富的炎性细胞类型，可促进肿瘤生长和转移。巨噬细胞向肿瘤中的募集由多种细胞因子介导，包括血管内皮生长因子（VEGF），认为其主要通过巨噬细胞上表达的VEGF受体（VEGFR）1发挥作用。巨噬细胞浸润受VEGF抑制的影响。我们发现，选择性抑制VEGFR2减少巨噬细胞浸润到原位胰腺肿瘤。我们的研究表明，肿瘤相关的巨噬细胞表达VEGFR2。此外，来自荷瘤动物的腹膜巨噬细胞表达VEGFR2，而来自非荷瘤动物的腹膜巨噬细胞不表达。据我们所知，这是第一次显示肿瘤相关巨噬细胞表达VEGFR2。此外，我们发现细胞因子多效因子足以诱导巨噬细胞上的VEGFR2表达。先前已显示多效生长因子诱导巨噬细胞上内皮细胞标志物的表达，并且存在于原位胰腺肿瘤的微环境中。最后，我们表明，VEGFR2，当由巨噬细胞表达时，是VEGF刺激的肿瘤相关巨噬细胞迁移所必需的。总之，肿瘤相关巨噬细胞表达VEGFR2，并且VEGFR2的选择性抑制减少巨噬细胞募集到原位胰腺肿瘤中。我们的研究结果表明，一个低估的作用机制，可能直接有助于血管生成抑制剂，阻断VEGFR2途径的抗肿瘤活性。
Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non-tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway.