Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.
Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.
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DOI：
10.1038/nature07445
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发表时间：
2008-12-11
期刊：
影响因子：
64.8
通讯作者：
Johnson, Randall S.
中科院分区：
文献类型：
--
作者：
Stockmann, Christian;Doedens, Andrew;Weidemann, Alexander;Zhang, Na;Takeda, Norihiko;Greenberg, Joshua I.;Cheresh, David A.;Johnson, Randall S.
血管生成和血管网络的发育是肿瘤进展所需的，并且涉及从恶性细胞和基质细胞类型释放血管生成因子，包括血管内皮生长因子（VEGF）。髓系细胞的浸润是许多肿瘤的标志，在许多情况下，这些浸润中的巨噬细胞表达VEGF。在这里，我们表明，炎症细胞源性VEGF的缺失减弱了典型的高密度血管网络的形成，从而阻断了实体瘤中的血管生成开关。缺乏髓系细胞来源的VEGF的肿瘤中的血管系统不那么曲折，周细胞覆盖增加，血管长度减少，表明血管正常化。此外，髓源性VEGF的缺失降低了肿瘤中的VEGFR2磷酸化，即使肿瘤中的总体VEGF水平不受影响。然而，髓样缺失VEGF导致在多个皮下同系移植模型和乳腺肿瘤发生的自体转基因模型中肿瘤进展加速，总体肿瘤细胞死亡减少，肿瘤缺氧减少。此外，髓样细胞VEGF的缺失增加了肿瘤对化疗细胞毒性的易感性。这表明骨髓来源的VEGF对于血管系统的致瘤性改变和VEGFR2的信号传导是必需的，并且这些变化起到延缓而不是促进肿瘤进展的作用。
Angiogenesis and the development of a vascular network is required for tumor progression, and involves release of angiogenic factors, including vascular endothelial growth factor (VEGF), from both malignant and stromal cell types. Infiltration by cells of the myeloid lineage is a hallmark of many tumors, and in many cases the macrophages in these infiltrates express VEGF. Here we show that deletion of inflammatory cell-derived VEGF attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumors. Vasculature in tumors lacking myeloid cell-derived VEGF was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF decreases VEGFR2 phosphorylation in tumors, even though overall VEGF levels in the tumors are unaffected. However, myeloid deletion of VEGF resulted in an accelerated tumor progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumor cell death and decreased tumor hypoxia. Furthermore, loss of myeloid cell VEGF increased tumor susceptibility to chemotherapeutic cytotoxicity. This demonstrates that myeloid-derived VEGF is essential for tumorigenic alteration of vasculature and signaling to VEGFR2, and that these changes act to retard, not promote, tumor progression.
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