Abstract
Glioblastoma (GBM) is a highly invasive brain tumor. Perivascular invasion, autovascularization and vascular co-option occur throughout the disease and lead to tumor invasion and progression. The molecular basis for perivascular invasion, i.e., the interaction of glioma tumor cells with endothelial cells is not well characterized. Recent studies indicate that glioma cells have increased expression of CXCR4. We investigated the in-vivo role of CXCR4 in perivascular invasion of glioma cells using shRNA-mediated knock down of CXCR4. We show that primary cultures of human glioma stem cells HF2303 and mouse glioma GL26-Cit cells exhibit significant migration towards human (HBMVE) and mouse (MBVE) brain microvascular endothelial cells. Blocking CXCR4 on tumor cells with AMD3100 in-vitro, inhibits migration of GL26-Cit and HF2303 toward MBVE and HBMVE cells. Additionally, genetic down regulation of CXCR4 in mouse glioma GL26-Cit cells inhibits their in-vitro migration towards MBVE cells; in an in-vivo intracranial mouse model, these cells display reduced tumor growth and perivascular invasion, leading to increased survival. Quantitative analysis of brain sections showed that CXCR4 knockdown tumors are less invasive. Lastly, we tested the effects of radiation on CXCR4 knock down GL26-Cit cells in an orthotopic brain tumor model. Radiation treatment increased apoptosis of CXCR4 downregulated tumor cells and prolonged median survival. In summary, our data suggest that CXCR4 signaling is critical for perivascular invasion of GBM cells and targeting this receptor makes tumors less invasive and more sensitive to radiation therapy. Combination of CXCR4 knock down and radiation treatment might improve the efficacy of GBM therapy.
Highlights
Glioblastoma (GBM) is an aggressive brain tumor with high morbidity and mortality rates
We show that primary cultures of human glioma stem cells HF2303 and mouse glioma GL26-Cit cells exhibit significant migration towards human (HBMVE) and mouse (MBVE) brain microvascular endothelial cells
We described that throughout glioma growth invasion occurs via auto-vascularization, a mechanism related to vessel co-option, by which glioma cells invade and allow brain tumor to become vascularized by normal blood vessels
Summary
Glioblastoma (GBM) is an aggressive brain tumor with high morbidity and mortality rates. These tumors are associated with poor prognosis due to their ability to migrate away from the central tumor and invade healthy brain tissue by growing within perivascular spaces through various mechanisms of perivascular invasion, i.e., vessel co-option and autovascularization [1,2,3,4]. Recent studies note that the progress of GBM is driven by glioblastoma stem-like cells (GSCs), critical promoters of tumor growth, invasion, and neovascularization [3, 7, 8, 17, 18]. This study explores the effects of C-X-C Chemokine Receptor 4, CXCR4 and its role in perivascular Invasion
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