Abstract 252: CXCL7-CXCR2 axis as a novel prognostic factor in myeloid cell associated glioblastoma
Authors: Achyut Bhagelu R. , Shankar Adarsh , Jain Meenu , Angara Kartik , Iskander ASM , Ara Roxan , Arbab Ali S. 
Published: July 2016

Glioblastoma (GBM), a grade IV glioma, is considered highly vascular and invasive subtype. GBM is most lethal during first year after initial diagnosis despite surgical resection, radiotherapy and/or chemotherapy. Antiangiogenic treatments (AATs) against VEGF-VEGFR pathways resulted into increased GBM tumor growth with marked hypoxia and increased recruitment of bone marrow derived cells (BMDCs) to the tumor microenvironment (TME), without any survival benefits.

Preclinical studies have found that AAT failures were associated with increased bone marrow-derived tumor-associated myeloid cells (TAMCs) in GBM. Depletion of CSF1R+ myeloid cells using GW2580 decreased recruitment of TAMCs in the tumor, and reduced GBM growth. Interestingly, AAT increased the expression of CXCL7 chemokine, and CSF1R blockade decreased CXCL7 in GBM microenvironment. In addition, CXCL7 expression was correlated with number of tumor infiltrating bone marrow derived cells, phospho-ERK MAPK expression, and proliferation of bone marrow cells in GBM.

Here, we looked at the prognostic significance of CXCL7 and its receptor CXCR2 in human GBM. We performed systematic human data analysis (www.oncomine.com), which revealed that CXCL7 is highly expressed (43 to 150 fold) in normal BM compared to other normal organs. This suggests that CXCL7 is required for BM cell survival and migration both in normal and tumor conditions. In GBM datasets, CXCL7 mRNA expression in tumor was increased (&gt; 4.5 fold) in GBM patients (n = 27) compared to normal brain (n = 4). CXCL7 mRNA expression was seen more in stroma (n = 4) than tumor cells (n = 5). Overall survival status analysis showed that patients with GBM who died early (n = 28) had significantly higher CXCL7 mRNA expression compared to living patients (n = 10). In addition, increased CXCL7 mRNA expression was associated with the GBM tumor recurrence (n = 8) compared to primary occurrence (n = 8). Interestingly, CXCL7 mRNA expression was correlated with the CXCR2 mRNA expression (CXCL7 receptor) both in normal (0.7, n = 71) and brain tumor tissues (0.6, n = 68). Similarly, CXCR2 mRNA expression was increased in GBM (n = 78) compared to other brain tumors. CXCR2 mRNA expression was seen more in stroma (n = 4) than tumor cells (n = 5). Patients with GBM, who died early (n = 19) had significantly higher CXCR2 mRNA expression compared to living patients (n = 10). In addition, increased CXCR2 mRNA expression was associated with the GBM tumor recurrence (n = 8) compared to primary occurrence (n = 8). However, data regarding the CXCL7 and CXCR2 expression in response to AATs is lacking in human cancer datasets.

In summary, we identified CXCL7-CXCR2 axis as a novel prognostic factor in GBM. However, studies are required to investigate CXCL7-CXCR2 regulation in myeloid cell survival/ polarization in TME.

Citation Format: Bhagelu R. Achyut, Adarsh Shankar, Meenu Jain, Kartik Angara, ASM Iskander, Roxan Ara, Ali S. Arbab. CXCL7-CXCR2 axis as a novel prognostic factor in myeloid cell associated 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 252.