MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Department of Hepatobilliary & Pancreatic Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Hepatology. 2019 Sep;70(3):824-839. doi: 10.1002/hep.30366. Epub 2019 Mar 15.
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.
索拉非尼是晚期肝细胞癌（HCC）的首选一线系统治疗药物。然而，目前尚无预测索拉非尼反应的临床应用生物标志物。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，而不依赖于癌细胞的迁移和浸润。在这项研究中，我们旨在探讨血管模式是否可以预测索拉非尼的获益。从四家学术医院招募了两组患者。研究了 VETC 模式（VETC/VETC ）患者接受索拉非尼治疗的生存获益。Kaplan-Meier 分析显示，索拉非尼治疗可显著降低死亡风险并延长总生存期（OS；在队列 1/2 中，P=0.004/0.005；风险比 [HR]为 0.567/0.408）和复发后生存期（PRS；在队列 1/2 中，P=0.001/0.002；HR 为 0.506/0.384）。然而，索拉非尼治疗对 VETC 患者无益（OS 在队列 1/2 中，P=0.204/0.549；HR 为 0.761/1.221；PRS 在队列 1/2 中，P=0.121/0.644；HR 为 0.728/1.161）。单因素和多因素分析均证实，索拉非尼治疗可显著改善 VETC 患者的 OS/PRS，但对 VETC 患者无效。进一步的机制研究表明，VETC 和 VETC HCC 肿瘤组织（pERK）或内皮细胞（EC-pERK）中 LC3 和磷酸化细胞外信号调节激酶（ERK）的水平相似，并且无论 pERK/EC-pERK/LC3 水平如何，VETC HCC 患者始终比 VETC 患者观察到更大的索拉非尼获益，这表明 VETC 和 VETC HCC 之间不同的索拉非尼获益可能不是由于 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/血管内皮生长因子受体 2（VEGFR2）/ERK 信号通路的激活或自噬的诱导引起的。结论：索拉非尼可有效延长 VETC 患者的生存时间，但不能延长 VETC 患者的生存时间。VETC 模式可能是预测 HCC 患者索拉非尼获益的标志物。
