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Abstract 2: CXCR2+ tumor cells mediate vascular mimicry driving anti-angiogenic therapy (AAT) resistance in glioblastoma (GBM)

2018; American Association for Cancer Research; Volume: 78; Issue: 13_Supplement Linguagem: Inglês

10.1158/1538-7445.am2018-2

1538-7445

Kartik Angara, Thaiz F. Borin, Mohammad H. Rashid, Roxan Ara, Bhagelu R. Achyut, Ali S. Arbab,

Glioma Diagnosis and Treatment

Abstract Glioblastoma (GBM) is a hypervascular and hypoxic neoplasia of the central nervous system with an extremely high rate of mortality. Owing to its hypervascularity, anti-angiogenic therapies (AAT) have been used as an adjuvant to the traditional surgical resection, chemotherapy, and radiation to normalize blood vessels and control abnormal vasculature. The benefits of AAT have been transient, and evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance and alternative neovascularization mechanisms in these resilient tumors to counter the AAT therapy insult. Vascular mimicry (VM) is the uncanny ability of tumor cells to acquire endothelial-like properties and lay down vascular patterned networks reminiscent of host endothelial blood vessels. The VM channels serve as an irrigation system for the tumors to meet with the increasing metabolic and nutrient demands of the tumor. In our current studies to understand the tumor-inherent mechanisms of AAT resistance, we identified a crucial pro-migratory and pro-angiogenic chemokine, CXCL8 or IL-8, to be highly upregulated in the GBM tumors treated with AAT. AAT-treated groups had significantly higher populations of CXCR2+ stem and endothelial-like subpopulations and these cells lined the VM-like vascular structures carrying functional RBCs in the tumors. These stem cell-like and endothelial-like populations were decreased following treatment with HET0016 or SB225002. Furthermore, knocking down CXCR2 led to smaller tumor size in the animals and improperly developed vascular structures without CXCR2+ GBM cells lining them. Also, HET0016 and SB225002 disrupt the tube-forming capability of U251 GBM cells in an in vitro Matrigel angiogenesis assay. This confirms our hypothesis that CXCR2+ GBM cells initiate VM and contribute to AAT resistance in GBM. Our present study suggests that tumor cell autonomous IL-8/CXCR2 pathway contributes to VM-mediated AAT resistance in GBM and that HET0016 and SB225002 have a great potential to target therapeutic resistance and can be combined with other chemotherapeutic agents in preclinical and clinical trials. Citation Format: Kartik P. Angara, Thaiz F. Borin, Mohammad H. Rashid, Roxan Ara, Bhagelu R. Achyut, Ali S. Arbab. CXCR2+ tumor cells mediate vascular mimicry driving anti-angiogenic therapy (AAT) resistance in glioblastoma (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2.