Combined inhibition of VEGF- and PDGF-signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms
Combined inhibition of VEGF- and PDGF-signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms
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DOI：
10.1096/fj.03-0271fje
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Vajkoczy, Peter
中科院分区：
文献类型：
--
作者：
Erber, Ralf;Thurnher, Andreas;Vajkoczy, Peter
现有肿瘤血管的破坏可以通过靶向血管内皮生长因子（VEGF）信号传导来实现，其不仅介导内皮细胞增殖，而且介导内皮细胞存活。然而，在这项研究中，活体显微镜未能证明靶向VEGFR-2（通过酪氨酸激酶抑制剂SU 5416）诱导实验性肿瘤血管的显著消退。免疫组织化学、电子显微镜、表达分析和原位杂交提供的证据表明，肿瘤血管对VEGFR-2靶向的这种抗性是由周细胞赋予的，周细胞通过Ang-1/Tie 2途径稳定血管并提供内皮细胞存活信号。相比之下，靶向VEGFR-2加上血小板衍生生长因子受体（PDGFR）-β系统（PDGFR-β）信号传导（通过SU 6668）迅速迫使40%的肿瘤血管消退，使这些肿瘤缺氧，如磷光淬灭所示。TUNEL染色、电子显微镜和细胞凋亡阻断实验表明，VEGFR-2加PDGFR-β靶向通过诱导内皮细胞凋亡来增强肿瘤血管消退。我们进一步表明，这是通过干扰周细胞-内皮细胞相互作用实现的。这项研究提供了对以下机制的新见解：1）周细胞如何为抗血管生成治疗提供逃逸策略; 2）不仅靶向内皮细胞，而且靶向参与血管稳定和成熟的周细胞相关途径的新概念发挥了有效的抗血管作用。
Destruction of existing tumor blood vessels may be achieved by targeting vascular endothelial growth factor (VEGF) signaling, which mediates not only endothelial cell proliferation but also endothelial cell survival. In this study, however, intravital microscopy failed to demonstrate that targeting of VEGFR-2 (by the tyrosine kinase inhibitor SU5416) induces significant regression of experimental tumor blood vessels. Immunohistochemistry, electron microscopy, expression analyses, and in situ hybridization provide evidence that this resistance of tumor blood vessels to VEGFR-2 targeting is conferred by pericytes that stabilize blood vessels and provide endothelial cell survival signals via the Ang-1/Tie2 pathway. In contrast, targeting VEGFR-2 plus the platelet-derived growth factor receptor (PDGFR)-beta system (PDGFR-beta) signaling (by SU6668) rapidly forced 40% of tumor blood vessels into regression, rendering these tumors hypoxic as shown by phosphorescence quenching. TUNEL staining, electron microscopy, and apoptosis blocking experiments suggest that VEGFR-2 plus PDGFR-beta targeting enforced tumor blood vessel regression by inducing endothelial cell apoptosis. We further show that this is achieved by an interference with pericyte-endothelial cell interaction. This study provides novel insights into the mechanisms of how 1) pericytes may provide escape strategies to anti-angiogenic therapies and 2) novel concepts that target not only endothelial cells but also pericyte-associated pathways involved in vascular stabilization and maturation exert potent anti-vascular effects.