Abstract
Abstract Glioblastoma (GBM) is the most aggressive of the primary brain tumors and carries a poor prognosis due to its highly infiltrative nature and tendency to progress. Glioma stem cells are a small tumor-initiating population in GBM whose properties are incompletely understood. Autocrine and paracrine factors associated with specific microenvironmental niches, such as the perivascular space and hypoxic regions, are thought to attract and support this stem cell component. Precise mechanisms guiding the homing to these niches have not been defined. Glioma stem cells express the receptor CXCR4, which initiates cell migration in the presence of the chemokine, stromal cell-derived factor-1α (SDF-1α). Both hypoxic and vascular regions in the brain express SDF-1α. Therefore, we hypothesize that glioma stem cells transplanted into the brain are driven by SDF-1α chemoattraction towards vascular and hypoxic niches. Cells were sorted for the stem cell marker CD133 using MACS for two explanted human GBM cell lines grown as neurospheres (N08-74 and N08-30). Sorted cells were compared to unsorted cells by Western blot for expression of CD133, hypoxia inducible factor-1α (HIF-1α), CXCR4 and stem cell markers under normoxia and hypoxia. Two million CD133-sorted cells suspended in PBS were delivered into the nasal mucosa of NOD/SCID mice to test cellular migration into the brain via intranasal transplantation. Coronal sections of brain tissue were analyzed at 12 hours after intranasal cell delivery. In both GBM cell lines (N08-30 and N08-74), we confirmed that sorted cells expressed more CD133 than unsorted cells and that both cell lines expressed CXCR4. Further, CXCR4 expression was significantly greater in the CD133-sorted N08-30 cells with a trend in an increase of c-Myc expression compared to unsorted cells. Hypoxic exposure of N08-74 CD133-sorted cells showed a trend of increased HIF-1α and c-Myc expression. In mice, we demonstrated that CD133-sorted cells can migrate into the brain when delivered intranasally. To show the potential for migration towards the vasculature, we show that SDF-1α is expressed in the brain vasculature in vivo. These data demonstrate that GBM cells can be sorted for CD133-positive glioma stem cells, respond to hypoxia, and express the SDF-1α receptor, CXCR4. In one cell line, CXCR4 expression increased after CD133 cell sorting. With intranasal delivery, CD133-sorted cells can migrate into the brain. Understanding the migration behavior of glioma stem cells relative to the diverse microenvironments has implications in treatment for targeting certain migratory populations or microenvironments. These data prepare the conditions to test the migratory potential of glioma stem cells in hypoxic and vascular environments in the brain. Citation Format: Monica J. Chau, Myles R. McCrary, Subhas Mukherjee, Daniel J. Brat. Microenvironmental influences on glioma stem cell migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5217. doi:10.1158/1538-7445.AM2015-5217
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