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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Neurosurgery, 2 Brain Tumor Center, and 3 Department of Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Frederick F. Lang, Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Unit 442, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2400; Fax: 713-745-4341; E-mail: flang{at}mdanderson.org.
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-1
, 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-ß (hMSC-IFN-ß). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-ß against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-ß 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.
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