title: VEGF regulates region-specific localization of perivascular bone marrow-derived cells in glioblastoma.
abstract: Glioblastoma multiforme (GBM) is characterized by a pathogenic vasculature that drives aggressive local invasion. Recent work suggests that GBM cells recruit bone marrow-derived progenitor cells (BMDC) to facilitate recurrence after radiotherapy, but how this may be achieved is unclear. In this study, we established the spatiotemporal and regional contributions of perivascular BMDCs (pBMDC) to GBM development. We found an increased recruitment of BMDCs to GBM in response to tumor growth and following radiotherapy. However, in this study, BMDCs did not differentiate into endothelial cells directly but rather provided a perivascular support role. The pBMDCs were shown to associate with tumor vasculature in a highly region-dependent manner, with central vasculature requiring minimal pBMDC support. Region-dependent association of pBMDC was regulated by VEGF. In the absence of VEGF, following radiotherapy or antiangiogenic therapy, we documented an increase in Ang2 that regulated recruitment of pBMDCs to maintain the vulnerable central vasculature. Together, our results strongly suggested that targeting pBMDC influx along with radiation or antiangiogenic therapy would be critical to prevent vascular recurrence of GBM.
authors.affiliation: Authors' Affiliations: Department of Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children;
authors.forename: Kelly
authors.initials: K
authors.lastname: Burrell
authors.affiliation: Authors' Affiliations: Department of Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children;
authors.forename: Sanjay
authors.initials: S
authors.lastname: Singh
authors.affiliation: Authors' Affiliations: Department of Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children;
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Jalali
authors.affiliation: Department of Medical Biophysics, Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto; and.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.affiliation: Authors' Affiliations: Department of Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children; Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada Gelareh.Zadeh@uhn.ca.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C555023:VPS51 protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins