五味子乙素抑制乳腺癌血管生成的关键信号通路研究

Inhibiting tumor angiogenesis is an effective method for treating advanced cancer. VEGF secreted by cancer cells is a key factor during angiogenesis. Multiple drugs targeting VEGF signaling pathways have been approved for clinical treatment. However, there are no effective anti-angiogenic drugs for breast cancer. Schisandrin B (Sch B) is a monomeric compound extracted from traditionally Chinese medicine Schisandra. We have published several papers on Sch B. We demonstrated that Sch B can inhibit lung metastasis of breast cancer, the molecular mechanism of which is that Sch B inhibited NOX4 enzyme activity. In a depth research, we found that Sch B can inhibit angiogenesis of breast cancer both in vivo and in vitro. NOX4-VEGF signaling axis is an important pathway regulating tumor angiogenesis, but there is no report in breast cancer. In this project, we will first verify that NOX4 plays an important role in breast cancer angiogenesis, and then by over expression or knockdown of NOX4 in breast cancer cells, we will confirm that Sch B inhibits breast cancer angiogenesis by regulating NOX4-VEGF signaling pathway. Finally, we will explore other possible signaling pathways in breast cancer except for NOX4. This project will show for the first time that NOX4 is a new target for anti-angiogenic treatment in breast cancer and Sch B is a novel inhibitor targeting tumor angiogenesis.

抑制肿瘤血管生成是治疗晚期肿瘤的有效方法之一。肿瘤细胞分泌的VEGF是新生血管生成的关键因子，多种以VEGF信号通路为靶点的药物已经用于临床。然而，乳腺癌治疗中目前尚缺乏理想的抗血管生成类药物。我们对传统中药五味子中提取的单体化合物五味子乙素进行的前期研究证实五味子乙素可以抑制乳腺癌转移，其分子机制是抑制了NOX4的酶活性。深入的研究表明五味子乙素在体内体外均能抑制乳腺癌的血管形成。NOX4-VEGF信号轴是调控肿瘤血管生成的重要通路，然而该信号轴在乳腺癌中的作用尚无人报道。本项目将首先验证NOX4在乳腺癌血管生成中的重要作用，然后通过高表达或敲低NOX4的细胞株证明五味子乙素通过调控NOX4-VEGF信号轴抑制了乳腺癌的血管形成。最后，我们将探索乳腺癌中五味子乙素调控的NOX4之外的其它信号通路。该项目将首次明确NOX4是抑制乳腺癌血管生成的新靶点及五味子乙素是一种新的血管生成抑制剂。

该项目从抗肿瘤血管形成的机理出发，研究五味子乙素通过抑制肿瘤血管形成而杀伤肿瘤的机制。在研究的过程中，我们发现钙池操纵性钙内流(store-operated Ca entry，SOCE)在抗血管生成治疗耐药中起到关键作用。后续的研究以此为基础展开。我们通过细胞实验、动物实验、原代肺癌细胞培养及原代细胞的动物实验（Hollow Fiber Assay）证明，一种临床广泛使用的药物环孢菌素A（CsA）跟克唑替尼联用后，可以显著增强克唑替尼的抗癌活性。在机制上，克唑替尼治疗引起钙离子内流入细胞，然后通过calcineurin- KSR2信号通路激活Erk1/2，进而导致肿瘤细胞的增殖和耐药。CsA有效阻断calcineurin-KSR2-Erk1 / 2信号传导，促进克唑替尼诱导的细胞凋亡和G2/M细胞周期阻滞。该研究结果提示，环孢菌素A和克唑替尼的联合治疗可能是靶向治疗MET扩增的肺癌患者的一种有效方法。另外，我们对2015年1月至2017年3月期间在我院接收过阿帕替尼治疗对32例肝癌病人进行了回顾性分析。阿帕替尼是一种已上市的抗血管生成药物，目前已经批准的适应症是胃癌。我们发现其在肝癌病人中也具有良好的治疗效果，其中5个病人达到了PR，14个病人达到了SD，其疾病控制率为60%，中位生存时间达到了13个月，超过了目前常规的治疗方案。该研究的结果表明，阿帕替尼在肝癌治疗上可能具有潜在的价值。