血管生成在胶质瘤浸润生长过程中起关键作用，阻断肿瘤血供是最具潜力的治疗策略。我们已经证明间充质干细胞可以作为表达免疫毒素的载体细胞，分泌重组免疫毒素VEGF-PE38的骨髓间充质干细胞能够特异性杀伤胶质瘤内皮血管。然而，研究表明恶性胶质瘤血管中不仅存在内皮血管，同时还存在拟态血管。只有对肿瘤内皮血管和拟态血管双重杀伤，才能较彻底地阻断血供从而遏制肿瘤生长。进一步体外研究证明，参与形成拟态血管的胶质瘤细胞表面EphA2受体特异性高度表达。由此，我们首次提出双特异性免疫毒素VEGF-EphrinA1-PE38同时阻断胶质瘤内皮血管和拟态血管的可能性。本项目拟构建稳定表达该双特异性免疫毒素的骨髓间充质干细胞，体内移植后观察是否对内皮血管和拟态血管具有双重杀伤效应，旨在获得该双价免疫毒素特异性靶向杀伤内皮血管和拟态血管的可靠证据及作用机制，探索胶质瘤抗血管治疗的新策略。

As is known to all that angiogenesis plays a key role in growth of malignant gliomas,and blocking the blood supply to glioma is the most promising treatment strategies. We have demonstrated hMSC may serve as an effective platform for the targeted delivery of immunotoxin and VEGF-PE38 secreting hMSCs was effective at killing endothelial cells in a malignant glioma tumor model. However, recent studies have reported a new tumor microcirculation pattern, vasculogenic mimicry (VM), in malignant glioma and other tumors which participate in tumor blood supply accompanied by endothelium-dependent blood vessels. Therapeutic strategies that target endothelial cells have no effect on tumor cells that engage in VM. Novel strategies both killing endothelium-dependent blood vessels and VM channels are in great demand.Further studies have found that the EphA2 receptor is overexpressed on tumor cells and plays an key role duiring VM. With this in mind, we hypothesize that dua-specific immunotoxin VEGF-EphrinA1-PE38 could target both endothelial cells and tumor cells that engage in VM. For this project, hMSCs were genetically manipulated with an lentival vector encoding VEGF-EphrinA1-PE38. resulting in higher efficiency and long-term expression of the novel dual-specific immunotoxin. The ex vivo and in vivo studies will confirmed the therapeutic efficacy and reveal the mechanism of killing both endothelium-dependent blood vessels and VM channels. providing a novel strategy of anti-angiogenesis therapy for malignant gliomas.