Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment
Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment
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DOI：
10.1158/2159-8290.cd-13-0782
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发表时间：
2014-06-01
期刊：
影响因子：
28.2
通讯作者：
Pikarsky, Eli
中科院分区：
文献类型：
--
作者：
Horwitz, Elad;Stein, Ilan;Pikarsky, Eli
肝细胞癌（HCC）的死亡率稳步上升，但晚期HCC的治疗选择有限。我们确定了一个子集的小鼠和人类肝癌窝藏VEGFA基因组扩增，显示不同的生物学特性。与常见的肿瘤扩增不同，这种扩增似乎通过异型旁分泌相互作用起作用;基质VEGF受体（VEGFR）响应肿瘤VEGF-A，产生肝细胞生长因子（HGF），其间接影响肿瘤细胞。VEGF-A抑制导致HGF下调和增殖减少，特别是在扩增子阳性小鼠HCC中。索拉非尼是治疗晚期肝癌的一线药物，靶向多种激酶，包括VEGF受体，但总体上只有轻微的有益作用。我们发现，VEGFA扩增特异性的小鼠和人类肝癌是明显敏感的索拉非尼。回顾性患者队列的FISH分析显示，索拉非尼治疗的VEGF扩增HCC患者的生存率显著提高，表明VEGFA扩增是HCC对VEGF-A阻断药物应答的潜在生物标志物。
Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplification, displaying distinct biologic characteristics. Unlike common tumor amplifi cations, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors ( VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplifi cation specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplifi cation is a potential biomarker for HCC response to VEGF- A- blocking drugs.