cAMP信号激动剂对恶性胶质瘤血管新生和血管正常化的影响及机制研究

Excessive angiogenesis and vascular abnormality are major malignant phenotypes of cancer. Inhibition of tumor angiogenesis and inducing normalization of tumor vessels are the two strategies that target tumor vessels. Malignant glioma is characterized by abnormal vasculature and rapid angiogenesis. At present, the drugs targeting the malignant glioma vessels are limited and the therapeutic effects of them are poor. Our previous researches show that the cAMP pathway plays a key role in inducing differentiation of malignant glioma cells. We find that cAMP activator can induce differentiation of glioma cells into mature astrocytes and inhibit their proliferation in vitro and in vivo. But the effect of cAMP pathway on angiogenesis of malignant glioma is not clear. Here we found that cAMP activator can effectively inhibit the malignant glioma angiogenesis in vitro and in vivo, respectively through tube formation assay and subcutaneous xenograft model. Through angiogenesis cytokine microarray，we identified that the downregulation of CXCL1 is mainly responsible for the angiogenesis inhibition mediated by cAMP activation. Next, we plan to explore whether cAMP activator can disturb the differentiation of glioma stem cells into vascular mimicry and induce the vessels normalization in glioma. Finally, we will elucidate the molecular mechanisms of the vascular normalization induced by cAMP activation. The completion of this project may provide a new therapeutic target and a therapeutic strategy for targeting glioma vessels.

肿瘤的血管增生和异常是肿瘤的恶性表型之一，抑制肿瘤血管增生和诱导肿瘤血管正常化是靶向肿瘤血管的两种策略。恶性胶质瘤是一类血管丰富的肿瘤，目前靶向恶性胶质血管的药物有限，且疗效不理想。申请者前期研究表明，环磷酸腺苷（cAMP）信号在诱导恶性胶质瘤分化中有关键作用， cAMP信号激动剂可以诱导恶性胶质瘤细胞分化为正常星型胶质细胞，在体内、体外模型中抑制恶性胶质瘤生长，但是cAMP信号通路对恶性胶质瘤血管的作用仍不清楚。本项目研究发现，在体外的小管形成实验和体内的裸鼠皮下成瘤实验中， cAMP信号激动剂能有效抑制恶性胶质瘤的血管新生，并通过细胞因子芯片鉴定出CXCL1的下调在其中发挥关键作用；接下来，我们计划进一步探索cAMP信号激动剂能否阻断胶质瘤干细胞分化为血管拟态，以及能否诱导恶性胶质瘤血管正常化，并阐明其中的分子机制。本项目的完成，有望为临床靶向恶性胶质瘤血管提供新的作用靶点和治疗策略。

恶性胶质瘤是及其致命的脑部肿瘤，中位生存期仅仅13个月，急需新的治疗策略改善预后。为恶性胶质瘤的患者的生存质量，开发潜在的恶性胶质瘤治疗策略，本研究聚焦恶性胶质瘤治疗，在研究过程中产生了两个子方向：即血管靶向治疗和免疫治疗分别进行了研究。分别发现了诱导分化剂和溶瘤病毒作为恶性胶质瘤治疗药物的治疗潜力及其机制，具体地：1）研究了cAMP信号激动剂作为诱导分化剂，对恶性胶质瘤血管生成和血管正常化的效应和机制研究；2）研究了溶瘤病毒对恶性胶质瘤微环境的免疫微环境的重塑作用，以及溶瘤病毒和免疫治疗的协同效应。溶瘤病毒子方向已发表高水平SCI论文2篇，我们鉴定了PTEN缺陷为溶瘤病毒治疗标志物，并阐明了溶瘤病毒的微环境重塑作用，这部分成果发表在Signal Transduction and Targeted Therapy杂志；发现了核酸依赖性抗病毒机制，为溶瘤病毒的增效提供了潜在的靶点，这部分成果在Cell Research杂志上发表。cAMP信号激动对恶性胶质瘤血管正常化的效应和机制研究内容正在投稿当中。