Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
Cancer Gene Ther. 2010 Mar;17(3):192-202. doi: 10.1038/cgt.2009.64. Epub 2009 Oct 23.
The disseminated neoplastic foci of malignant gliomas are essentially responsible for the limited efficacy of current available therapeutic modalities. Bone marrow-derived stem cells (BMSCs) have the ability to migrate into these tumors and even track infiltrating tumor cells, making them to be promising cellular vehicles for delivering therapeutic agents to glioma cells. The herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) suicide gene therapy with a potent bystander effect has been considered as one of the most promising therapeutic strategies for malignant gliomas. In this study, we evaluate the anti-glioma effect of suicide gene therapy using BMSCs expressing HSV-TK combined with overexpression of connexin 43 (Cx43), which can restore the gap junction of intercellular communication and may enhance the bystander effect of suicide gene therapy. To assess the potential of BMSCs to track glioma cells, a spheroid co-culture system in matrigel was used to show that some BMSCs migrated to C6 glioma cell microspheres. Transwell assay showed the tumor tropic property of BMSCs. In addition, BrdU-labeled BMSCs injected directly into the cerebral hemisphere opposite to the established C6 rat gliomas were capable of migrating into the xenograft gliomas. C6 cell growth was more intensively inhibited by HSV-TK/GCV treatment mediated by BMSCs, and could be further enhanced by combination with Cx43 transfection into glioma cells. The same result was observed in vivo by the growth of C6 gliomas and the survival analysis of rats bearing C6 glioma. In conclusion, Cx43 combined with HSV-TK/GCV gene therapy using BMSCs as vehicles was highly effective in a rat glioma model and therefore hold great potential as a novel approach for the gene therapy of human malignant gliomas.
恶性神经胶质瘤的弥散性肿瘤灶是目前可用治疗方法疗效有限的主要原因。骨髓来源的干细胞（BMSCs）具有迁移到这些肿瘤中甚至追踪浸润肿瘤细胞的能力，使它们成为向神经胶质瘤细胞递送治疗剂的有前途的细胞载体。具有强大旁观者效应的单纯疱疹病毒胸苷激酶（HSV-TK）/更昔洛韦（GCV）自杀基因治疗被认为是恶性神经胶质瘤最有前途的治疗策略之一。在这项研究中，我们评估了表达 HSV-TK 的 BMSCs 与连接蛋白 43（Cx43）过表达相结合的自杀基因治疗对神经胶质瘤的抗瘤作用，这可以恢复细胞间通讯的间隙连接，并可能增强自杀基因治疗的旁观者效应。为了评估 BMSCs 追踪神经胶质瘤细胞的潜力，使用 Matrigel 中的球体共培养系统表明，一些 BMSCs 迁移到 C6 神经胶质瘤细胞微球中。Transwell 测定表明 BMSCs 具有肿瘤趋向性。此外，直接注射到已建立的 C6 大鼠神经胶质瘤对侧大脑半球的 BrdU 标记的 BMSCs 能够迁移到异种移植神经胶质瘤中。HSV-TK/GCV 治疗介导的 BMSCs 更强烈地抑制 C6 细胞的生长，并且通过与 Cx43 转染到神经胶质瘤细胞中结合可以进一步增强。在体内通过 C6 神经胶质瘤的生长和携带 C6 神经胶质瘤大鼠的生存分析观察到相同的结果。总之，用 BMSCs 作为载体结合 Cx43 的 HSV-TK/GCV 基因治疗在大鼠神经胶质瘤模型中非常有效，因此作为人类恶性神经胶质瘤基因治疗的新方法具有很大的潜力。
