Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma
Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma
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DOI：
10.1172/jci42405
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Heymach, John V.
中科院分区：
文献类型：
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作者：
Cascone, Tina;Herynk, Matthew H.;Heymach, John V.
血管生成对于肿瘤生长和转移是关键的，并且血管生成的几种抑制剂目前在临床上用于治疗癌症。然而，并不是所有的患者都能从抗血管生成治疗中获益，那些最初对治疗有反应的肿瘤最终会产生耐药性。这背后的机制，以及肿瘤细胞和间质对耐药的相对贡献尚未完全了解。在这里，使用人肺腺癌小鼠异种移植模型的物种特异性分析，我们已经表明，与获得性耐药VEGF抑制剂贝伐单抗相关的基因表达变化主要发生在间质细胞，而不是肿瘤细胞。特别是，EGFR和FGFR途径的组分在基质中上调，但在肿瘤细胞中不上调。在获得性耐药的异种移植物的周细胞和具有相对原发性耐药的肿瘤的内皮细胞上检测到增加的活化EGFR。获得性阻力与周细胞覆盖的正常化血运重建模式相关，而在相对原发性阻力中观察到迂曲、未覆盖的血管。重要的是，VEGF和EGFR通路的双重靶向降低了周细胞覆盖率并增加了无进展生存期。这些发现表明，肿瘤间质通路（包括EGFR和FGFR通路）的改变与VEGF抑制剂耐药相关，并可能导致耐药，靶向这些通路可能改善治疗疗效。了解基质信号可能是开发血管生成抑制剂的生物标志物和改善联合治疗方案的关键。
Angiogenesis is critical for tumor growth and metastasis, and several inhibitors of angiogenesis are currently in clinical use for the treatment of cancer. However, not all patients benefit from antiangiogenic therapy, and those tumors that initially respond to treatment ultimately become resistant. The mechanisms underlying this, and the relative contributions of tumor cells and stroma to resistance, are not completely understood. Here, using species-specific profiling of mouse xenograft models of human lung adenocarcinoma, we have shown that gene expression changes associated with acquired resistance to the VEGF inhibitor bevacizumab occurred predominantly in stromal and not tumor cells. In particular, components of the EGFR and FGFR pathways were upregulated in stroma, but not in tumor cells. Increased activated EGFR was detected on pericytes of xenografts that acquired resistance and on endothelium of tumors with relative primary resistance. Acquired resistance was associated with a pattern of pericyte-covered, normalized revascularization, whereas tortuous, uncovered vessels were observed in relative primary resistance. Importantly, dual targeting of the VEGF and EGFR pathways reduced pericyte coverage and increased progression-free survival. These findings demonstrated that alterations in tumor stromal pathways, including the EGFR and FGFR pathways, are associated with, and may contribute to, resistance to VEGF inhibitors and that targeting these pathways may improve therapeutic efficacy. Understanding stromal signaling may be critical for developing biomarkers for angiogenesis inhibitors and improving combination regimens.