Miletic Hrvoje, Fischer Yvonne, Litwak Sara, Giroglou Tsanan, Waerzeggers Yannic, Winkeler Alexandra, Li Huongfeng, Himmelreich Uwe, Lange Claudia, Stenzel Werner, Deckert Martina, Neumann Harald, Jacobs Andreas H, von Laer Dorothee
Abteilung für Neuropathologie, Universität zu Köln, Köln, Germany.
Mol Ther. 2007 Jul;15(7):1373-81. doi: 10.1038/sj.mt.6300155. Epub 2007 Apr 24.
Adult stem cells are promising cellular vehicles for therapy of malignant gliomas as they have the ability to migrate into these tumors and even track infiltrating tumor cells. However, their clinical use is limited by a low passaging capacity that impedes large-scale production. In the present study, a bone marrow-derived, highly proliferative subpopulation of mesenchymal stem cells (MSCs)-here termed bone marrow-derived tumor-infiltrating cells (BM-TICs)-was genetically modified for the treatment of malignant glioma. Upon injection into the tumor or the vicinity of the tumor, BM-TICs infiltrated solid parts as well as the border of rat 9L glioma. After intra-tumoral injection, BM-TICs expressing the thymidine kinase of herpes simplex virus (HSV-tk) and enhanced green fluorescent protein (BM-TIC-tk-GFP) were detected by non-invasive positron emission tomography (PET) using the tracer 9-[4-[(18)F]fluoro-3-hydroxymethyl)butyl]guanine ([(18)F]FHBG). A therapeutic effect was demonstrated in vitro and in vivo by BM-TICs expressing HSV-tk through bystander-mediated glioma cell killing. Therapeutic efficacy was monitored by PET as well as by magnetic resonance imaging (MRI) and strongly correlated with histological analysis. In conclusion, BM-TICs expressing a suicide gene were highly effective in the treatment of malignant glioma in a rat model and therefore hold great potential for the therapy of malignant brain tumors in humans.
成体干细胞是治疗恶性胶质瘤很有前景的细胞载体，因为它们有能力迁移到这些肿瘤中，甚至追踪浸润性肿瘤细胞。然而，它们的临床应用受到传代能力低的限制，这阻碍了大规模生产。在本研究中，对一种骨髓来源的、具有高增殖能力的间充质干细胞亚群（MSC）——此处称为骨髓来源的肿瘤浸润细胞（BM-TIC）——进行基因改造以治疗恶性胶质瘤。将BM-TIC注射到肿瘤或肿瘤附近后，它们浸润了大鼠9L胶质瘤的实体部分以及边界。瘤内注射后，使用示踪剂9-[4-[(18)F]氟-3-羟甲基)丁基]鸟嘌呤（[(18)F]FHBG），通过非侵入性正电子发射断层扫描（PET）检测到表达单纯疱疹病毒胸苷激酶（HSV-tk）和增强型绿色荧光蛋白的BM-TIC（BM-TIC-tk-GFP）。表达HSV-tk的BM-TIC通过旁观者介导的胶质瘤细胞杀伤在体外和体内都显示出治疗效果。通过PET以及磁共振成像（MRI）监测治疗效果，且与组织学分析密切相关。总之，表达自杀基因的BM-TIC在大鼠模型中治疗恶性胶质瘤非常有效，因此在人类恶性脑肿瘤治疗中具有巨大潜力。
