Brown Alice B, Yang Wendy, Schmidt Nils O, Carroll Rona, Leishear Kim K, Rainov Nikolai G, Black Peter M, Breakefield Xandra O, Aboody Karen S
Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Hum Gene Ther. 2003 Dec 10;14(18):1777-85. doi: 10.1089/104303403322611782.
The remarkable migratory and tumor-tropic capacities of neural stem cells (NSCs and/or neuroprogenitor cells) represent a potentially powerful approach to the treatment of invasive brain tumors, such as malignant gliomas. We have previously shown that whether implanted directly into or at distant sites from an experimental intracranial glioma, NSCs distributed efficiently throughout the main tumor mass and also tracked advancing tumor cells, while stably expressing a reporter transgene. As therapeutic proof-of-concept, NSCs genetically modified to produce the prodrug activating enzyme cytosine deaminase (CD), effected an 80% reduction in the resultant tumor mass, when tumor animals were treated with the systemic prodrug, 5-fluorocytosine. We now extend our findings of the tumor-tropic properties of NSCs (using a well-characterized, clonal NSC line C17.2), by investigating their capacity to target both intracranial and extracranial tumors, when administered into the peripheral vasculature. We furthermore demonstrate their capacity to target extracranial non-neural tumors such as prostate cancer and malignant melanoma. Well-characterized NSC lines (lacZ and/or CD-positive) were injected into the tail vein of adult nude mice with established experimental intracranial and/or subcutaneous flank tumors of neural and non-neural origin. The time course and distribution of NSCs within the tumor and internal organs was assessed in various models. Resulting data suggest that NSCs can localize to various tumor sites when injected via the peripheral vasculature, with little accumulation in normal tissues. Our findings suggest the novel use of intravascularly administered NSCs as an effective delivery vehicle to target and disseminate therapeutic agents to invasive tumors of neural and nonneural origin, both within and outside of the brain.
神经干细胞（NSCs和/或神经祖细胞）卓越的迁移能力和肿瘤趋向性，为侵袭性脑肿瘤（如恶性胶质瘤）的治疗提供了一种潜在的有效方法。我们之前已经表明，无论将神经干细胞直接植入实验性颅内胶质瘤内还是植入远离肿瘤的部位，它们都能有效地分布于整个主要肿瘤块中，还能追踪迁移的肿瘤细胞，同时稳定表达报告转基因。作为治疗概念验证，经基因改造可产生前药激活酶胞嘧啶脱氨酶（CD）的神经干细胞，在用全身前药5-氟胞嘧啶治疗荷瘤动物时，可使肿瘤体积减少80%。现在，我们通过研究经外周血管给药时神经干细胞靶向颅内和颅外肿瘤的能力，扩展了我们对神经干细胞肿瘤趋向性特性（使用特性明确的克隆神经干细胞系C17.2）的研究结果。我们还证明了它们靶向颅外非神经肿瘤（如前列腺癌和恶性黑色素瘤）的能力。将特性明确的神经干细胞系（β-半乳糖苷酶和/或CD阳性）注入患有已建立的实验性颅内和/或皮下侧腹神经源性和非神经源性肿瘤的成年裸鼠尾静脉。在各种模型中评估神经干细胞在肿瘤和内部器官中的时间进程和分布。所得数据表明，经外周血管注射时，神经干细胞可定位于各种肿瘤部位，而在正常组织中几乎没有积聚。我们的研究结果表明，血管内给药的神经干细胞可作为一种有效的递送载体，将治疗药物靶向递送至脑内和脑外神经源性和非神经源性侵袭性肿瘤。
