Abstract 3275: Chemokine CXCL12 promotes vascular compensation in antiangiogenic resistance through CXCR7 in glioblastoma
Authors: Aleksandra B. Gruslova, David Cavasoz, Andrew Brenner
Journal: Cancer Research (2016)

Abstract Introduction: While antiangiogenic therapy has become an integral part of therapy for malignancy, it has failed to result in a proven survival benefit for glioblastoma (GBM). Recent studies have suggested a role for the chemokine CXCL12 in both de novo and acquired antiangiogenic resistance. To assess the impact of CXCL12 signaling on the vasculature and its ability to recruit progenitor cells, we combined a fluorescent chimeric mouse model and in vivo imaging to capture the chronological interactions among tumor cells (RFP), circulating BMDCs (GFP) and the cerebral vessels (FITC dextran) during tumor growth. Methods: For chimeric mice, bone marrow from Tie2_GFP mice were transplanted to athymic nude mice after 6Gy irradiation. After 6 weeks U251 glioma cells were stereotactically injected into the brain cortex, followed by installation of a cranial window. In vivo imaging was performed weekly (before, during and after treatment) on a confocal microscope. 3D projected images were processed for the determination of tumor and vasculature characteristics. To validate the role of two CXCL12 receptors we used sunitinib (VEGFR inhibitor), AMD3100 (CXCR4 inhibitor), CCX662 (CXCR7 inhibitor) alone or in combination. Results: Inhibition of VEGFR by sunitinib leads not only to a significant decrease in the number of small vessels as previously published, but also a statistically significant increase in size of the large vessels. Addition of CXCR7 inhibition to VEGFR inhibition prevented this adaptive vasculomegaly, but did not impact the loss of smaller vessels. In turn, CXCR4 inhibition had no effect on the vasculature. Further, CXCR7 inhibition decreases the number of BMDCs within vasculature, while CXCR4 inhibition decreased the number of cells recruited outside the vessels and into the tumor itself. These tumoral BMDCs are Iba1 positive and suggest a role of CXCR4 in recruitment of microglia. 3D analysis of cranial window images showed that while VEGFR inhibition slows tumor growth, and inhibition of CXCR4 or CXCR7 was not additive to this effect. In fact, inhibition of CXCR4 resulted in significant increase in tumor size perhaps through and impact on infiltration. Conclusions: Our results suggests a compensatory response of vasculomegaly to trimming of small vessels by sunitinib may be mediated by CXCL12 in a CXCR7 dependent process. CXCR7's effect on the number of BMDCs within the vessels suggests that the impact on vasculomegaly may be due to recruitment of endothelial progenitor cells into vessels or their survival following recruitment. In turn, VEGFR inhibition affects recruitment of progenitor cells outside the vessels in a CXCR4 dependent fashion. We propose that CXCL12 receptors, CXCR4 and CXCR7, have unique roles in response to loss of VEGF signaling and subsequent hypoxia. Further studies into the interplay between VEGFR, CXCL12, compensatory vasculomegaly, and vascular cooption are needed. Citation Format: Aleksandra B. Gruslova, David Cavasoz, Andrew Brenner. Chemokine CXCL12 promotes vascular compensation in antiangiogenic resistance through CXCR7 in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3275.