The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non-Small Cell Lung Cancer.
The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non-Small Cell Lung Cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-16-3216
复制
发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Heymach JV
中科院分区：
文献类型：
--
作者：
Cascone T;Xu L;Lin HY;Liu W;Tran HT;Liu Y;Howells K;Haddad V;Hanrahan E;Nilsson MB;Cortez MA;Giri U;Kadara H;Saigal B;Park YY;Peng W;Lee JS;Ryan AJ;Jüergensmeier JM;Herbst RS;Wang J;Langley RR;Wistuba II;Lee JJ;Heymach JV
对血管内皮生长因子受体（VEGFR）抑制剂的耐药性是非小细胞肺癌（NSCLC）治疗的主要障碍。我们研究了介导NSCLC对VEGFR酪氨酸激酶抑制剂耐药的细胞机制。我们建立了人NSCLC的鼠模型，并使用VEGFR TKI西地尼布和凡德他尼进行了靶向抑制研究。我们使用物种特异性杂交的微阵列来比较TKI敏感和耐药肿瘤的癌（人）和基质（小鼠）细胞转录组。我们测量了肿瘤微血管密度和血管迂曲度，以表征治疗对肿瘤血管床的影响。入组VEGFR TKI试验的患者的循环细胞因子和血管生成因子水平与临床结局相关。人肺腺癌的小鼠异种移植模型最初对VEGFR TKI敏感，但对治疗产生耐药性。种属特异性微阵列分析鉴定了基质源性肝细胞生长因子（HGF）表达增加作为TKI抗性的候选介质，其受体c-MET在癌细胞和肿瘤相关基质中被激活。缺氧调节分子在初始反应阶段的短暂增加，随后是适应性变化，导致更曲折的血管。癌细胞中的强制HGF表达降低了肿瘤对VEGFR TKI的敏感性，并产生了血管迂曲的肿瘤。双重VEGFR/c-MET信号传导抑制延迟了耐药表型的发生并防止了血管形态学改变。在接受VEGFR TKI治疗的癌症患者中，治疗前HGF血浆水平较高与生存率较差相关。HGF/c-MET通路介导非小细胞肺癌的VEGFR耐药和血管重构
Resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors. We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes. Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In cancer patients receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. HGF/c-MET pathway mediates VEGFR inhibitor-resistance and vascular remodeling in NSCLC.