Abstract 1425: Impact of VEGFR pathway inhibition on the expression and function of CXCR4 in primary patient derived glioblastoma cell lines.
Authors: Pham Kien , Luo Defang , Siemann Dietmar , Reynolds Brent A. , Hothi Parvinder , Foltz Gregory , Harrison Jeffrey K. 
Published: August 2014

Abstract
Glioblastoma (GBM) is one of the most malignant and aggressive forms of primary brain tumors. Current standard treatment options for patients diagnosed with GBM include surgical resection, radiation, and chemotherapy. Since GBM features an extensively vascularized solid tumor, anti-angiogenic agents have also been considered as a treatment regimen for GBM patients. Indeed, evidence from clinical trials has shown that Bevacizumab (Avastin®), an anti-VEGF monoclonal antibody, successfully reduces the development of tumor microvascular networks and prolongs the progression-free survival rate of GBM patients. In a subset of patients, however, tumors become resistant to this treatment and exhibit a more infiltrative phenotype after anti-angiogenic therapy. A recent published study (Lu et. al., Cancer Cell, 22:21; 2012) proposed that the HGF/c-MET signaling pathway may be involved in this enhanced invasive phenotype post anti-angiogenic therapy targeting VEGFRs. These data suggest that integrating VEGFR and c-MET inhibitors will prevent tumor recurrence from anti-angiogenic therapy. Because of the heterogeneity of the tumor microenvironment and complexity in signaling communication among cancer cells, we are interested in the contribution of chemokines and chemokine receptors in this phenomenon. Characterization of several primary patient-derived glioblastoma cell lines indicated heterogeneity in the level of expression of VEGFRs: some lines were VEGFR positive while others were VEGFR negative. VEGF and c-MET mRNAs were detected in all lines. Flow cytometry analysis of chemokine receptors indicated that levels of CXCR4 were elevated after VEGF/VEGFR inhibitor treatment (Bevacizumab, Cediranib or Vandetanib) only in VEGFR-expressing GBM cell lines, while CXCR7 was not affected by VEGFR pathway inhibition. In addition, VEGFR inhibitor treatment enhanced the migration of VEGFR-expressing lines to CXCL12. c-MET inhibitors did not impact VEGFR inhibitor-stimulated CXCR4 expression, suggesting that this regulation is independent of c-MET. Together, our data suggest that the CXCL12/CXCR4 axis may be an additional potential factor contributing to the invasive phenotype in recurrent tumors after anti-angiogenic therapy. Thus, the combination of VEGFR pathway inhibitors and CXCR4 antagonists may provide an alternative strategy to halt tumor progression and provide benefit to patients with GBM.
Citation Format: Kien Pham, Defang Luo, Dietmar Siemann, Brent A. Reynolds, Parvinder Hothi, Gregory Foltz, Jeffrey K. Harrison. Impact of VEGFR pathway inhibition on the expression and function of CXCR4 in primary patient derived glioblastoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1425. doi:10.1158/1538-7445.AM2013-1425