title: CXCL12 mediates trophic interactions between endothelial and tumor cells in glioblastoma.
abstract: Emerging evidence suggests endothelial cells (EC) play a critical role in promoting Glioblastoma multiforme (GBM) cell proliferation and resistance to therapy. The molecular basis for GBM-EC interactions is incompletely understood. We hypothesized that the chemokine CXCL12 and its receptor CXCR4 could mediate direct interactions between GBM cells and tumor-associated endothelial cells and that disruption of this interaction might be the molecular basis for the anti-tumor effects of CXCR4 antagonists. We investigated this possibility in vivo and in an in vitro co-culture model that incorporated extracellular matrix, primary human brain microvascular ECs (HBMECs) and either an established GBM cell line or primary GBM specimens. Depletion of CXCR4 in U87 GBM cells blocked their growth as intracranial xenografts indicating that tumor cell CXCR4 is required for tumor growth in vivo. In vitro, co-culture of either U87 cells or primary GBM cells with HBMECs resulted in their co-localization and enhanced GBM cell growth. Genetic manipulation of CXCL12 expression and pharmacological inhibition of its receptors CXCR4 and CXCR7 revealed that the localizing and trophic effects of endothelial cells on GBM cells were dependent upon CXCL12 and CXCR4. These findings indicate that the CXCL12/CXCR4 pathway directly mediates endothelial cell trophic function in GBMs and that inhibition of CXCL12-CXCR4 signaling may uniquely target this activity. Therapeutic disruption of endothelial cell trophic functions could complement the structural disruption of anti-angiogenic regimens and, in combination, might also improve the efficacy of radiation and chemotherapy in treating GBMs.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Shyam
authors.initials: S
authors.lastname: Rao
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Sengupta
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Choe
authors.forename: B Mark
authors.initials: BM
authors.lastname: Woerner
authors.forename: Erin
authors.initials: E
authors.lastname: Jackson
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Leonard
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
mesh_terms: D015153:Blotting, Western; D001921:Brain / Q000098:blood supply; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D055806:Microvessels / Q000166:cytology; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D017931:DNA Primers; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4