Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy.
Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy.
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表皮生长因子受体抑制通过血管正常化调节微环境，从而提高化疗和放疗疗效。
DOI：
10.1371/journal.pone.0006539
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发表时间：
2009-08-06
期刊：
影响因子：
3.7
通讯作者：
Maity, Amit
中科院分区：
文献类型：
--
作者：
Cerniglia, George J.;Pore, Nabendu;Tsai, Jeff H.;Schultz, Susan;Mick, Rosemarie;Choe, Regine;Xing, Xiaoman;Durduran, Turgut;Yodh, Arjun G.;Evans, Sydney M.;Koch, Cameron J.;Hahn, Stephen M.;Quon, Harry;Sehgal, Chandra M.;Lee, William M. F.;Maity, Amit
表皮生长因子受体（EGFR）抑制剂在作为单一药物用于治疗癌症时仅显示出适度的临床活性。它们降低肿瘤细胞缺氧诱导因子1-α（HIF-1α）和血管内皮生长因子（VEGF）的表达。假设这可能使肿瘤血管正常化，我们检查了EGFR抑制剂厄洛替尼对肿瘤血管功能、肿瘤微环境（TME）以及化疗和放疗敏感性的影响。厄洛替尼在体外治疗人肿瘤细胞和在体内治疗荷瘤小鼠导致HIF-1α和VEGF表达降低。治疗改变了通过共聚焦显微镜（番茄凝集素注射后）评估的异种移植血管形态，并降低了血管通透性（通过伊文思蓝外渗测量），表明血管正常化。通过能量多普勒超声测量，厄洛替尼增加了肿瘤血流量，通过EF 5免疫组织化学测量和通过光学光谱测量的肿瘤O2饱和度降低了缺氧。预测这些变化将改善药物递送并增加对化疗和放疗的反应，我们在用厄洛替尼和放疗或化疗剂顺铂治疗的异种移植物的裸鼠中进行了肿瘤再生长研究。与单独治疗相比，厄洛替尼治疗后顺铂导致肿瘤生长的协同抑制（p<0.001）。在顺铂之前用厄洛替尼治疗导致比在厄洛替尼之前用顺铂治疗更大的肿瘤生长抑制（p = 0.006）。 厄洛替尼随后放射抑制肿瘤再生长的程度比单独放射更大，尽管厄洛替尼和放射之间的相互作用不是协同的。EGFR抑制剂与常规细胞毒性治疗联合使用时已显示出临床获益。我们的研究表明，用EGFR抑制剂靶向肿瘤细胞可以通过血管正常化来调节TME，以增加对化疗和放疗的反应。这些研究提出了使用TME的非侵入性成像来评估肿瘤对EGFR抑制的反应的方法。
Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O2 saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic. EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.
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