Abstract
Abstract Glioblastoma multiforme is one of the most aggressive and fatal brain cancers mostly because of the highly invasive nature of glioma cells. The ability of glioma cells to disperse to healthy brain stroma makes surgical and chemotherapeutic treatments mostly ineffective. Microglia infiltrate most gliomas and release factors, which favor tumor growth and dispersal. We hypothesize that microglia residing within the tumor stimulate glioma cell migration and dispersal through the phospholipase C (PLC)γ1 and proline rich tyrosine kinase 2 (Pyk2) signaling cascade. In the present study, we investigated rodent C6 and GL261 as well as human glioma cell lines with varying levels of invasiveness: U-87MG, A172, and HS683. Using a standard invasion assay, we demonstrated that the presence of rodent or immortalized human microglia in the bottom compartment of Boyden chambers activated invasion of all glioma cell types. Knock-down of PLCγ1 and Pyk2 proteins using siRNA reversed the stimulatory effect of microglia on glioma invasion in both cell lines. Pharmacological blockers of PLC (U73872 1nM) and Pyk2/focal adhesion kinase (FAK) (PF562271 20nM) also completely eliminated the ability of microglia to stimulate glioma cell migration in a wound healing assay. Using Western blot, we found upregulation of phosphorylated Tyr579/580 Pyk2 protein in glioma cells treated with microglia conditioned medium. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 and PLCγ1 signaling pathway in glioma cells. This research was made possible by NIH grant numbers: G11 HD052352, G12 RR03035, 8G12MD007583-27, U54 NS039408, UCC Pilot Project Program and Title V PPOHA grant number P031M105050 from the US Dept. of Education. Citation Format: Kimberleve Rolon-Reyes, Miguel Mendez, David E. Rivera-Aponte, Serguei N. Skatchkov, Misty J. Eaton, Lilia Kucheryavykh. Microglia promote glioma cell migration and dispersal by activating the PLCγ1 and Pyk2 signaling cascade. [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 1644. doi:10.1158/1538-7445.AM2013-1644
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