title: Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.
abstract: BACKGROUND
  In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.
  
  
  METHODS
  We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro.
  
  
  RESULTS
  CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.
  
  
  CONCLUSIONS
  These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Walters
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ebsworth
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Berahovich
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: M E T
authors.initials: ME
authors.lastname: Penfold
authors.affiliation: Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: S-C
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: R
authors.initials: R
authors.lastname: Al Omran
authors.affiliation: Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kioi
authors.affiliation: Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Chernikova
authors.affiliation: Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tseng
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Mulkearns-Hubert
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sinyuk
authors.affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: J
authors.initials: J
authors.lastname: Karamchandani
authors.affiliation: Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: H E K
authors.initials: HE
authors.lastname: Kohrt
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Powers
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Jaen
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Schall
authors.affiliation: Department of Neurology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: M
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Department of Neurology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: L
authors.initials: L
authors.lastname: Recht
authors.affiliation: Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D054371:Chemokine CXCL11 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D054387:Receptors, CXCR