title: Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism.
abstract: Purpose:One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs) which are highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPC). The development and molecular signature of NPC-derived glioblastomas were analyzed and the therapeutic effect of blocking CXCL12 was tested.Experimental Design:Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis, and expression of proteins regulating survival and cell-cycle progression.Results:Tumors induced from NPCs display histologic features of human glioblastoma and express markers of GSLC.In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals.In vitro, CXCR4 blockade induces apoptosis and inhibits cell-cycle progression, downregulates molecules regulating survival and proliferation, and also blocks the hypoxic induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation.Conclusions:This study demonstrates that the CXCL12/CXCR4 axis operates in glioblastoma cells under hypoxic stress via an autocrine-positive feedback mechanism, which promotes survival and cell-cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced glioblastoma progression, prevent resistance to treatment, and recurrence of the disease.Clin Cancer Res; 23(5); 1250-62. ©2016 AACR.
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Anda-Alexandra
authors.initials: AA
authors.lastname: Calinescu
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Viveka Nand
authors.initials: VN
authors.lastname: Yadav
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Erica
authors.initials: E
authors.lastname: Carballo
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Padma
authors.initials: P
authors.lastname: Kadiyala
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Dustin
authors.initials: D
authors.lastname: Tran
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Zamler
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Robert
authors.initials: R
authors.lastname: Doherty
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Maithreyi
authors.initials: M
authors.lastname: Srikanth
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.|Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Pedro Ricardo
authors.initials: PR
authors.lastname: Lowenstein
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan. mariacas@med.umich.edu.|Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Maria Graciela
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D058953:Neural Stem Cells / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics*; D015398:Signal Transduction; D019895:Transposases / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D019895:Transposases; C494471:sleeping beauty transposase, human