肝癌组织VETC对靶向药物治疗应答的预测作用及其潜在机制

Molecular targeted medicine is the recommended therapy for metastatic and recurrent hepatocellular carcinoma (HCC), and sorafenib is the only approved targeted medicine to treat HCC nowadays. However there is no biomarker to predict its efficacy. Our recent work found that the special microvessel type VETC is an important factor to promote tumor recurrence and metastasis, and sorafenib is more effective on HCC patients with VETC in the tumor. The preliminary mechanism study showed that the expression of chemokine receptors CXCR4 closely related with VETC, and sorafenib could induce apoptosis of CXCR4+ endothelial cells (ECs). Therefore we assume that sorafenib could affect formation of VETC by interfering the CXCR4 highly expressing ECs, then suppress the progression and metastasis of HCC. At the same time, VETC and CXCR4 can be used to predict the clinical efficacy of sorafenib. This study intends to complete: 1. To detect the expression of CXCR4 in the VETC structure, and their relationship with efficacy of sorafenib in HCC; 2. To perform in vitro study to reveal the molecular mechanism of sorafenib functioning on the CXCR4 ECs; 3. To observe the effect of sorafenib on CXCR4+ ECs and VETC formation in animal models; 4. To verify the role of VETC and CXCR4 as predictive biomarkers for sorafenib treatment. Our results are expected to reveal a new mechanism to treat HCC, as well as to provide the evidence to use VETC and CXCR4 as clinical indicators of sorafenib usage.

靶向药物是转移和复发性肝癌的推荐治疗，但缺乏疗效预测指标。肝癌组织VETC微血管结构是促进肿瘤复发转移的重要因素，而存在VETC的患者对索拉非尼治疗受益更为明显，初步机制研究表明内皮细胞趋化因子受体CXCR4的表达与VETC的形成密切相关，而索拉非尼可选择性诱导CXCR4+内皮细胞的凋亡。我们设想：索拉非尼可通过影响表达CXCR4的内皮细胞，干扰VETC结构形成来抑制肝癌的进展转移，从而改善患者生存，而VETC及CXCR4可作为预测其疗效的指标。本研究拟完成：1.临床样本检测CXCR4在肝癌组织VETC结构中的表达及其与索拉非尼疗效的关系；2.体外实验明确索拉非尼影响CXCR4表达的机制；3.小鼠模型观察索拉非尼对CXCR4及VETC形成的影响；4.临床研究验证VETC及CXCR4作为疗效预测靶标的价值，结果有望揭示肝癌靶向治疗的新机制，为VETC及CXCR4作为疗效预测靶标提供依据。

包绕肿瘤细胞团的微血管网（vessels that encapsulate tumor cluster，VETC）是肝细胞癌的一种独特血管结构，伴有此血管结构的肿瘤细胞团可通过非侵袭依赖的转移方式直接脱落进入血管形成癌栓，与患者的术后复发和不良预后呈现显著正相关。我们发现具有VETC结构的肝癌的血管内皮细胞高表达趋化因子受体 CXCR4 分子，索拉非尼则能够显著诱导 CXCR4+内皮细胞的凋亡。本研究结合临床多中心队列研究、动物模型和体外实验，明确了CXCR4在VETC形成中具有重要的促进作用，发现肿瘤调节性巨噬细胞分泌的炎症性细胞因子可促进内皮细胞表达CXCR4，并证实索拉非尼可通过抑制ERK的磷酸化，下调CXCR4表达以提高治疗敏感性，而联合应用索拉非尼及巨噬细胞拮抗剂唑来膦酸（ZA）可抑制血管CXCR4表达，增强索拉非尼的抗肿瘤活性。多中心临床研究验证了VETC作为预测索拉非尼疗效指标的价值，即VETC+的肝细胞癌患者可以从索拉非尼治疗中获益，而VETC-患者服用索拉非尼无生存获益。体内实验表明索拉非尼可有效破坏小鼠肝癌VETC结构及减少VETC形成，从而减少肝癌转移的发生。进一步的探索发现高表达Fms样酪氨酸激酶3（Fms-like tyrosine kinase 3, FLT-3）的患者接受索拉非尼治疗后可获得较好的生存预后，提示FLT3或可作为预测索拉非尼疗效的新的生物标记物。以上发现有助于改变目前肝癌患者盲目选择靶向药物的现状，对实现肝癌的精准治疗具有重要意义，本课题组将对VETC及FLT3对于肝癌其他靶向药物治疗的预测价值开展进一步研究。