Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma
Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma
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封装肿瘤簇 (VETC) 模式的血管是索拉非尼对肝细胞癌患者获益的预测因子
DOI：
10.1002/hep.30366
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发表时间：
2019-09-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
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作者：
Fang, Jian-Hong;Xu, Li;Zhuang, Shi-Mei
索拉非尼是晚期肝细胞癌（HCC）最受推荐的一线全身治疗药物。然而，目前临床上尚无用于预测索拉非尼疗效的生物标志物。我们已经证明，一种名为VETC（包裹肿瘤簇的血管）的血管模式有助于将整个肿瘤簇释放到血液中；VETC介导的转移依赖于血管模式，而非癌细胞的迁移和侵袭。在本研究中，我们旨在探讨血管模式是否能够预测索拉非尼的疗效。从四家学术医院招募了两组患者。研究了具有或不具有VETC模式（VETC + /VETC -）的患者使用索拉非尼治疗的生存获益情况。Kaplan - Meier分析显示，索拉非尼治疗显著降低了VETC +患者的死亡风险，延长了总生存期（在队列1/2中，P = 0.004/0.005；风险比[HR] = 0.567/0.408）和复发后生存期（在队列1/2中，P = 0.001/0.002；HR = 0.506/0.384）。然而，索拉非尼治疗对VETC -患者没有益处（在队列1/2中，总生存期P = 0.204/0.549；HR = 0.761/1.221；在队列1/2中，复发后生存期P = 0.121/0.644；HR = 0.728/1.161）。单因素和多因素分析证实，索拉非尼治疗显著改善了VETC +患者的总生存期/复发后生存期，但对VETC -患者没有改善。进一步的机制研究表明，VETC +和VETC - HCC在肿瘤组织中的轻链3（LC3）和磷酸化细胞外信号调节激酶（ERK）（pERK）或内皮细胞（EC - pERK）水平相似，并且无论pERK/EC - pERK/LC3水平如何，在VETC + HCC患者中始终观察到比VETC -患者更大的索拉非尼获益，这表明VETC +和VETC - HCC之间索拉非尼获益的差异可能不是由于Raf/丝裂原活化蛋白激酶激酶（MEK）/ERK和血管内皮生长因子（VEGF）A/VEGF受体2（VEGFR2）/ERK信号通路的激活或自噬的诱导。结论：索拉非尼可有效延长VETC +患者的生存期，但对VETC -患者无效。VETC模式可能作为HCC索拉非尼获益的预测指标。
Sorafenib is the most recommended first-line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC-mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+/VETC-) was investigated. Kaplan-Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC- patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+, but not VETC-, patients. Further mechanistic investigations showed that VETC+ and VETC- HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal-regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC-pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC- irrespective of levels of pERK/EC-pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC- HCCs may not result from activation of Raf/mitogen-activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+, but not VETC-, patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.