Nakamizo Akira, Marini Frank, Amano Toshiyuki, Khan Asadullah, Studeny Matus, Gumin Joy, Chen Julianne, Hentschel Stephen, Vecil Giacomo, Dembinski Jennifer, Andreeff Michael, Lang Frederick F
Department of Neurosurgery, Brain Tumor Center, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer Res. 2005 Apr 15;65(8):3307-18. doi: 10.1158/0008-5472.CAN-04-1874.
The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
人类恶性胶质瘤患者生存率低，部分原因在于无法将治疗药物输送至肿瘤部位。鉴于有研究表明，循环骨髓源干细胞可因组织应激而被募集至实体器官，我们推测人类骨髓源间充质干细胞（hMSC）可能对脑肿瘤具有趋向性，因此可作为胶质瘤治疗的药物递送载体。为验证此推测，我们从正常志愿者的骨髓中分离出hMSC，对细胞进行荧光标记，然后将其注入携带人胶质瘤颅内异种移植物（U87、U251和LN229）的小鼠颈动脉。无论细胞是注入同侧还是对侧颈动脉，hMSC都仅出现在脑肿瘤内。相比之下，颈动脉内注射成纤维细胞或U87胶质瘤细胞会导致递送的细胞广泛分布，而无肿瘤特异性。为评估hMSC追踪人类胶质瘤的潜力，我们将hMSC直接注入已形成的人类胶质瘤对侧的大脑半球，结果显示hMSC能够在体内迁移至异种移植物中。同样，体外基质胶侵袭实验表明，胶质瘤条件培养基而非成纤维细胞或星形胶质细胞条件培养基能支持hMSC迁移，血小板衍生生长因子、表皮生长因子或基质细胞衍生因子-1α可增强hMSC迁移，而碱性成纤维细胞生长因子或血管内皮生长因子则无此作用。为测试hMSC递送治疗药物的潜力，我们对hMSC进行基因改造使其释放IFN-β（hMSC-IFN-β）。体外共培养和Transwell实验显示了hMSC-IFN-β对人类胶质瘤的疗效。体内实验表明，与对照组相比，用hMSC-IFN-β治疗人U87颅内胶质瘤异种移植物可显著提高动物生存率（P < 0.05）。我们得出结论，hMSC经血管内或局部递送后可整合至人类胶质瘤中，这种植入可能由生长因子介导，hMSC对人类胶质瘤的这种趋向性可用于治疗优势。
