Human Mesenchymal Stem Cell Homing to Glioma Stem Cell Xenografts

Abstract

Glioblastoma (GBM) is the most common adult primary brain tumor with a median survival of approximately one year. The current standard of care for GBM includes the maximal surgical resection, followed by concurrent chemotherapy, radiotherapy, and in some cases and adjuvant chemotherapy. Yet, despite this aggressive multimodal approach, GBM is a nearly universally fatal disease. The poor outcome is in large part due to the lack of effective therapeutic agents that can penetrate the blood-brain and blood-tumor barriers to deliver anti-glioma therapeutics to the whole tumor and the microsatellite populations of tumor cells scattered throughout the brain parenchyma. However, bone marrow-derived human mesenchymal stem cells (hMSCs) offer a viable alternative to enhance therapeutic delivery – one that overcomes current limitations. hMSCs are a population of cells with the capability of self-renewal and multilineage differentiation that can be safely isolated in routine clinical procedures and pose no ethical quandaries. hMSCs demonstrate an intrinsic tropism towards gliomas and are capable of migrating across the blood-brain and blood-tumor barriers. These cells have been used as delivery vehicles to convey immunotherapy, enzymes for chemotherapeutic pro-drugs, and oncolytic viruses with some success in pre-clinical models.
Despite the promise of hMSCs, previous studies have relied for the most part on xenografts derived from commercially available immortalized GBM cell lines. These cell lines poorly mimic patient tumors in vivo and thus do not adequately translate into the clinical setting. Glioma stem cells (GSCs) rectify this shortcoming by faithfully recapitulating the genotype and phenotype of the human tumor from which they were isolated. However, studies from our collaborators at MD Anderson Cancer Center show that hMSCs demonstrate variable tropism towards GSC-derived tumors (GSC xenografts; GSCXs). Those GSC xenografts that attract hMSCs are referred to as ‘attractors’, whereas those that fail to evoke hMSC homing are designated ‘non-attractors’. The underlying biological mechanism of hMSCs differential homing capacity towards GSCXs is virtually unknown. Given the clinical potential of hMSCs as therapeutic delivery vehicles of anti-glioma agents, the rationale behind this project was to elucidate the molecular mechanisms that underlie the variable localization of hMSCs to gliomas by use of GSCXs as a clinically relevant brain tumor model. The long-term goal is to understand the essential factors in hMSC homing to gliomas, in order to successfully harness hMSCs for clinical use or to identify patients most appropriate for hMSC-mediated therapeutic delivery. This work is significant because the outcomes will identify differences between attractor and non-attractor GSCXs, which will be critical in advancing our knowledge for continued development of hMSCs as a viable therapeutic strategy.

Description
Keywords
Glioblastoma, Glioma stem cells, xenografts, bone marrow-derived mesenchymal stem cells, homing, lipidomics, proteomics, transcriptomics
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