Abstract 1973: Influences of extracellular matrix protein tenascin-c on glioblastoma stem cell growth and invasion through tumor-microenvironment interactions

Abstract

Abstract Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumors in adults. Recent research on cancer stroma indicates that brain microenvironment plays substantial roles in brain tumor malignancy and treatment responses to current anti-tumor therapy. In this work, we investigated the effect of changes in tenascin-C (TNC), a multimodular glycoprotein found in malignant brain tumor extracellular matrix, on GBM proliferation, differentiation, and migration in vitro and in vivo. We studied TNC gain-of-function and loss-of function in GBM stem-like neurospheres, whose in vivo growth pattern closely replicates human GBM. We found that TNC was significantly down-regulated (30-40%) during differentiation of GBM stem cells in response to serum or retinoic acid. TNC knockdown with shRNA had no effect on cell growth in vitro. Yet, under differentiation conditions, TNC knockdown strongly promoted cell adhered to laminin-coated surfaces, and increased GFAP expression by ∼20-fold. These suggest that endogenous TNC is important to promote the differentiation and attachment of GBM stem cells in response to differentiation stimuli. We further found that TNC loss-of-function promoted GBM stem cell adhesion and actin cytoskeleton organization via the activation of focal adhesion kinase (FAK) pathway as FAK pathway inhibitors significantly inhibited (>75%) TNC knockdown mediated cell adhesion. We further investigate the effect of TNC loss-of-function on intracranial xenografts derived from GBM stem cells. When TNC expression was decreased in tumor microenvironment, we detected decreased tumor cell invasion accompanied by increased tumor size. In vitro and in vivo studies confirmed our hypothesis that decreased TNC in tumor microenvironment significantly altered the interactions between tumor cells and their surrounding non-tumor cells including endothelial and microglial cells, and therefore influenced tumor growth pattern. In summary, we found that TNC is not involved in GBM stem cell proliferation and maintenance, but rather in GBM stem cell adhesion and migration in vitro. TNC loss-of-function promotes GBM stem cell adhesion and differentiation. Decreased TNC expression in brain tumor microenvironment prevents tumor cell migration and invasion, but alters tumor cell-endothelial/microglial cell interactions, which results in increased tumor growth. A full understanding of how TNC in tumor microenvironment influences the interactions between tumor cells and their surrounding non-tumor cells will ultimately lead to novel combinatory anti-tumor strategies to treat malignant brain tumors. Note: This abstract was not presented at the meeting. Citation Format: Shervin Wang, Bachchu Lal, Brian Tung, John Laterra, Shuli Xia. Influences of extracellular matrix protein tenascin-c on glioblastoma stem cell growth and invasion through tumor-microenvironment interactions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1973. doi:10.1158/1538-7445.AM2014-1973