Introduction: Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Recent research on cancer stroma indicates that the brain microenvironment plays a substantial role in brain tumor malignancy and treatment responses to current anti-tumor therapy. In this work, we investigated the effect of alterations in brain tumor extracellular matrix tenascin (TNC) on brain tumor growth patterns including proliferation and invasion. TNC is a multimodular glycoprotein found in malignant brain tumors and mediates cell-cell and cell-matrix interactions.

Methods: We studied TNC gain-of-function and loss-of function in GBM stem-like neurospheres (GSCs), whose in vivo growth pattern closely replicates human GBM.

Results: TNC knockdown with shRNAs promoted GSC adhesion and actin cytoskeleton organization. Inhibition of focal adhesion kinase (FAK) pathway activation significantly inhibited (>75%) TNC knockdown-mediated cell adhesion. Yet, TNC loss-of-function or exogenous TNC had no effect on cell growth in vitro. The effect of TNC loss-of-function on in vivo tumor growth was assessed using GSC intracranial xenografts. When TNC expression was decreased in the tumor microenvironment, we detected decreased tumor cell invasion accompanied by increased tumor size, suggesting that TNC regulates the “go-or-grow” phenotypic switch of GSC in vivo. We further demonstrate that decreased TNC in the tumor microenvironment significantly altered the interactions between tumor cells and surrounding non-tumor endothelial and microglial cells, influencing the tumor growth pattern.

Conclusions: Our findings suggest that increased understanding of how TNC in the tumor microenvironment influences interactions between tumor cells and surrounding non-tumor cells will benefit novel combinatory anti-tumor strategies to treat malignant brain tumors.

Patient Care: This research will improve patient care by elucidating the interactions between tumor cells and surrounding non-tumor cells that will influence the development and utilization of novel combination anti-tumor strategies to treat malignant brain tumors.

Learning Objectives: By the conclusion of this session, participants should be able to describe the influence of TNC in the tumor microenvironment on interactions between malignant brain tumor cells and surrounding non-tumor cells.

References: References 1. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. Aug 2011;59(8):1169-1180. 2. Lorger M. Tumor microenvironment in the brain. Cancers. 2012;4(1):218-243. 3. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. The international journal of biochemistry & cell biology. Jun 2004;36(6):1046-1069. 4. Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clinical cancer research : an official journal of the American Association for Cancer Research. Oct 1 2011;17(19):6125-6129. 5. Zamecnik J. The extracellular space and matrix of gliomas. Acta neuropathologica. Nov 2005;110(5):435-442. 6. Brellier F, Chiquet-Ehrismann R. How do tenascins influence the birth and life of a malignant cell? Journal of cellular and molecular medicine. Jan 2012;16(1):32-40. 7. Behrem S, Zarkovic K, Eskinja N, Jonjic N. Distribution pattern of tenascin-C in glioblastoma: correlation with angiogenesis and tumor cell proliferation. Pathology oncology research : POR. 2005;11(4):229-235. 8. Leins A, Riva P, Lindstedt R, Davidoff MS, Mehraein P, Weis S. Expression of tenascin-C in various human brain tumors and its relevance for survival in patients with astrocytoma. Cancer. Dec 1 2003;98(11):2430-2439. 9. Brosicke N, van Landeghem FK, Scheffler B, Faissner A. Tenascin-C is expressed by human glioma in vivo and shows a strong association with tumor blood vessels. Cell and tissue research. Nov 2013;354(2):409-430. 10. Varga I, Hutoczki G, Szemcsak CD, et al. Brevican, neurocan, tenascin-C and versican are mainly responsible for the invasiveness of low-grade astrocytoma. Pathology oncology research : POR. Apr 2012;18(2):413-420. 11. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. Nov 18 2004;432(7015):396-401. 12. Huang Z, Cheng L, Guryanova OA, Wu Q, Bao S. Cancer stem cells in glioblastoma--molecular signaling and therapeutic targeting. Protein & cell. Jul 2010;1(7):638-655. 13. Bar EE, Chaudhry A, Lin A, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells. Oct 2007;25(10):2524-2533. 14. Sun P, Xia S, Lal B, et al. DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation. Stem Cells. Jul 2009;27(7):1473-1486. 15. Ying M, Wang S, Sang Y, et al. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene. Aug 4 2011;30(31):3454-3467. 16. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. Dec 7 2006;444(7120):756-760. 17. Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. Mar 28 2013;153(1):139-152. 18. Ying M, Sang Y, Li Y, et al. Kruppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells. Stem Cells. Jan 2011;29(1):20-31. 19. Chiquet-Ehrismann R, Matsuoka Y, Hofer U, Spring J, Bernasconi C, Chiquet M. Tenascin variants: differential binding to fibronectin and distinct distribution in cell cultures and tissues. Cell regulation. Nov 1991;2(11):927-938. 20. Pollard SM, Yoshikawa K, Clarke ID, et al. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell stem cell. Jun 5 2009;4(6):568-580. 21. Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer research. Oct 1 2004;64(19):7011-7021. 22. Hirata E, Arakawa Y, Shirahata M, et al. Endogenous tenascin-C enhances glioblastoma invasion with reactive change of surrounding brain tissue. Cancer science. Aug 2009;100(8):1451-1459. 23. Kim MY, Kim OR, Choi YS, et al. Selection and characterization of tenascin C targeting peptide. Molecules and cells. Jan 2012;33(1):71-77. 24. Rolle K, Nowak S, Wyszko E, et al. Promising human brain tumors therapy with interference RNA intervention (iRNAi). Cancer biology & therapy. Mar 1 2010;9(5):396-406. 25. Zukiel R, Nowak S, Wyszko E, et al. Suppression of human brain tumor with interference RNA specific for tenascin-C. Cancer biology & therapy. Aug 2006;5(8):1002-1007.