Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism.

Autor:	Calinescu AA; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Yadav VN; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Carballo E; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Kadiyala P; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Tran D; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Zamler DB; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Doherty R; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Srikanth M; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan., Lowenstein PR; 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., Castro MG; 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.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Mar 01; Vol. 23 (5), pp. 1250-1262. Date of Electronic Publication: 2016 Aug 19.
DOI:	10.1158/1078-0432.CCR-15-2888
Abstrakt:	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 . (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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