Abstract
Glioblastoma multiforme (GBM) is a lethal brain tumor. Radiation therapy has been an essential part of treatment for glioma patients. Despite high radiation therapy along with anticancer drugs, GBMs invariably recur. Glioma Stem Cells (GSCs) resistant to chemo and radiation therapies are mainly responsible for GBM recurrence. Therefore, increase sensitivity of GBM cells to radiation and/chemo therapies could be of therapeutic value. We have recently described that GBM derived glioma stem cells grow along blood vessels (Baker et al, 2014). In this study we observed that different primary human glioma stem cell lines, HF2303, MSP-12, IN859 and IN2045, and a mouse glioma Gl26-cit cell line, showed significant directional migration towards human and mouse brain-derived endothelial (MBVE) cells. To uncover the mechanism of GBM cell migration, we tested the role of various chemokines and inhibitors utilizing in vitromigration assays. Notably, migration of Gl26-cit and HF2303 towards MBVE was significantly inhibited by AMD3100 (CXCR4 inhibitor). We further confirmed these findings by knocking down of CXCR4 in GL26-cit cells using shRNA. The migration of CXCR4 knock-down in GL26-cit-shCXCR4 cells towards MBVE was significantly reduced compared to control shRNA treated Gl26-cit cells (Gl26-cit-NT). We next established an orthotopic brain tumor in mice using GL26-cit-shCXCR4 and Gl26-cit-NT cells. Mice implanted with down regulated CXCR4 GL26-cit-shCXCR4 cells exhibited prolonged survival compared to Gl26-cit-NT mice. Brain section analysis showed that GL26-cit-shCXCR4 cells are less invasive. Lastly, we tested the effect of radiation on mice implanted with GL26-cit-shCXCR4 or Gl26-cit-NTcells. Mice implanted with GL26-cit-shCXCR4 cells showed further improvement in survival compared to Gl26-cit-NT tumor-bearing mice upon radiation. In summary, CXCR4-CXCL12 signaling is critical for the perivascular invasion of GBM cells and targeting this axis makes tumors less invasive and more sensitive to radiation therapy. Targeting CXCR4-CXCL12 signaling could be a potential therapeutic strategy for treatment of GBM.
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