胶质母细胞瘤分泌sLRIG2调控血管内皮细胞Axl信号通路促进血管生成的机制

Robust angiogenesis is one of the hallmarks of glioblastoma and anti-angiogenic therapy is an important therapeutic strategy for patients with glioblastoma. Pro-angiogenic factors, which are secreted from tumors and exert their biological activities through the receptor tyrosine kinases (RTKs) in the endothelial cells, play a vital role in the angiogenesis of tumors. However, the effects of anti-angiogenic therapeutic strategies targeting the single angiogenic factor signaling pathway are unsatisfactory. Recently, we have for the first time demonstrated that soluble LRIG2 ectodomain (sLRIG2) is capable of being released from glioblastoma cells and promote the growth of glioblastoma through regulating multiple receptor tyrosine kinases. Further, we found that sLRIG2, secreted from gliblastoma cells, could promote the tube formation ability of human brain microvascular endothelial cells (hBMECs) and enhanced the Axl phosphorylation of endothelial cells. Axl plays a pivotal role in the angiogenesis of tumors, however the specific functions of Axl in angiogenesis of glioma and the underlying mechanisms remain largely unexplored. We propose that sLRIG2, secreted from glioblastoma cells, regulate the Axl signaling pathways in endothelial cells to promote the angiogenesis of glioblastoma. This project is to investigate the effects of sLRIG2 on the angiogenesis of glioblastoma and its mechanisms by which sLRIG2 is secreted from glioblastoma cells and regulates the Axl signaling pathways in endothelial cells. The findings will contribute to a better understanding of the regulatory mechanisms of angiogenesis in glioblastoma and provide an attractive therapeutic target for future treatment of glioblastoma.

胶质母细胞瘤最主要的病理特征之一为活跃的血管生成，抑制血管生成是其重要的临床治疗策略。肿瘤分泌的促血管生成因子作用于血管内皮细胞上相应的酪氨酸激酶受体（RTKs）对肿瘤血管生成起重要作用。然而拮抗单一的生长因子信号通路在胶质瘤的临床治疗效果中并不理想。课题申请人发现胶质母细胞瘤细胞可分泌sLRIG2蛋白，调控多种RTK，促进胶质瘤细胞生长。进一步研究发现胶质瘤细胞分泌的sLRIG2可促进人脑微血管内皮细胞管样结构生成及上调血管内皮细胞中Axl磷酸化水平。Axl在肿瘤的血管生成中起重要作用，但其在胶质瘤血管生成中的具体功能及机制尚不清楚。我们推测胶质母细胞瘤细胞可分泌sLRIG2调控血管内皮细胞Axl信号通路促进肿瘤血管生成。本研究探讨胶质母细胞瘤分泌sLRIG2的机制，及其调控血管内皮细胞中Axl信号通路促进血管生成的机制，有助于丰富胶质瘤血管生成的调控机制，发现新的抗血管生成治疗靶点。

胶质母细胞瘤（Glioblastoma, GBM）是成人最常见的原发恶性中枢神经系统肿瘤，活跃的血管生成是其最主要的病理特征。肿瘤微环境中的促血管生成因子作用于血管内皮细胞上的酪氨酸激酶受体（RTKs）对肿瘤血管生成起重要作用，然而目前靶向单一血管生成相关因子有其信号通路的抗血管生成治疗并不理想。项目负责人前期发现胶质母细胞瘤可分泌sLRIG2蛋白且可调控胶质瘤肿瘤细胞多种RTK促进肿瘤生长。因此研究胶质瘤分泌的多RTK信号通路调控蛋白影响血管生成的机制对改善胶质瘤抗血管生成治疗效果具有重要意义。.本项目主要研究胶质母细胞瘤中sLRIG2蛋白分泌机制，以及离体和在体水平研究sLRIG2作用于血管内皮细胞Axl受体对胶质瘤血管生成的影响及其机制。.胶质母细胞瘤细胞可通过水解酶途径分泌sLRIG2蛋白于肿瘤的微环境中，并作用于肿瘤微血管内皮细胞上的Axl受体，激活Axl及其下游信号Akt，Stat3信号通路，从而促进肿瘤内皮细胞的增殖、迁移和微血管形成能力。抑制Axl信号通路活化可明显抑制GBM中sLRIG2的促血管生成能力。我们还通过本项目扩展研究发现LRIG2还可调控GBM肿瘤细胞的PDGFRβ促进胶质瘤的生以及Axl信号通路以促进胶质瘤的化疗抵抗。.sLRIG2作为胶质母细胞瘤肿瘤细胞分泌到微环境中一种新的可分泌性蛋白，在调控胶质母细胞瘤的血管生成中发挥重要作用，同时其分泌前的全长LRIG2蛋白还可调控GBM细胞多种受体酪氨酸激酶促进GBM恶性进展，sLRIG2/LRIG2有望为抑制胶质瘤的血管生成及恶性进展提供新的治疗靶点。