CXCL12/CXCR4 signaling axis in NPC-derived GBM

Purpose: One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs), highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPCs). The development and molecular signature of NPC-derived GBMs 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 histological features of human GBM 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 GBM 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 GBM progression, prevent resistance to treatment and recurrence of the disease.

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