Abstract
Abstract Tumor-associated macrophages/microglia (TAMs) are either macrophages of peripheral origin or brain-intrinsic microglia, and represent a considerable portion of the glioma mass, which facilitate gliomagenesis. Chemokine C-C motif ligand 5 (CCL5) is an inflammatory mediator produced by immune cells, and involves in tumor growth, and migration in serval cancers including glioma. However, the mechanism of how CCL5 facilitates glioma invasion remains largely unresolved. In this study, we demonstrate that CCL5 modulate human glioma cell lines, A172 and U87, migratory and invasive activities along with MMPs expression. In response to CCL5, glioma synchronized an increase of intracellular calcium levels, and kinase elevations including p-CaMKII, and p-Akt expressions in time and dosage manners. Importantly, glioma invasion along with MMPs elevation are dependent on CCL5-propogated p-CaMKII expression, and inhibition of p-CaMKII effectively reduced CCL5-directed glioma MMPs expression and invasion. Using three-dimensional cultures, we demonstrated that glioma cells tend to homing toward GM-CSF-activated TAM condition media. This homing effect associated with MMPs elevation which can be ameliorated either by controlling the intracellular and extracellular calcium levels or by CCL5 antagonism. Clinical results also reveal association of CCL5 with TAM activation, and patients' overall survival. Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma migration and could be a potential therapeutic strategy for alleviating glioma invasion. Citation Format: Caren Yu-Ju Wu, Chia-Hua Chen, Chun-Yen Lin, Li-Ying Feng, Yung-Chang Lin, Kuo-Chen Wei, Chiung-Yin Huang, Jia-You Fang, Pin-Yuan Chen. CCL5 from tumor-associated macrophages/microglia (TAMs) regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase-2 [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 3794.
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