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Targeting Hyaluronan Interactions for Glioblastoma Stem Cell Therapy

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Cancer Microenvironment

Abstract

Even with rigorous treatments, glioblastoma multiforme (GBM) has an abysmal median survival rate, greatly due to the drug-resistant glioblastoma stem cell (GSC) population. GSCs are known to remodel their microenvironment, but the precise role of extracellular matrix components hyaluronic acid (HA) and hyaluronidases (HAases) on the GSC population is still largely unknown. Our objective was to determine how HAase can sensitize GSCs to chemotherapy drugs by disrupting the HA-CD44 signaling. GBM cell line U87-MG and patient-derived D456 cells were grown in GSC-enriching media and treated with HA or HAase. Expressions of GSC markers, HA-related genes, and drug resistance genes were measured via flow cytometry, confocal microscopy, and qRT-PCR. Proliferation after combined HAase and temozolomide (TMZ) treatment was measured via WST-8. HA supplementation promoted the expression of GSC markers and CD44 in GBM cells cultured in serum-free media. Conversely, HAase addition inhibited GSC gene expression while promoting CD44 expression. Finally, HAase sensitized GBM cells to TMZ. We propose a combined treatment of HAase and chemotherapy drugs by disrupting the stemness-promoting HA to target GSCs. This combination therapy shows promise even when temozolomide treatment alone causes resistance.

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Acknowledgements

The authors would like to thank Dr. G. Yancey Gillespie (University of Alabama at Birmingham) for providing the D456 patient-derived xenograft GBM line. The authors would like to further acknowledge financial support from the National Science Foundation (CBET 1604677 to Y.K. and S.R.), the University of Alabama Randall Research Scholars Program (J.S.H.), and by the Alabama Experimental Program to Stimulate Competitive Research (S.P.). S.D.G.

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  1. Department of Chemical and Biological Engineering, The University of Alabama, Box 870203, Tuscaloosa, AL, 35487-0203, USA

    Joline S. Hartheimer, Seungjo Park, Shreyas S. Rao & Yonghyun Kim

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Hartheimer, J.S., Park, S., Rao, S.S. et al. Targeting Hyaluronan Interactions for Glioblastoma Stem Cell Therapy. Cancer Microenvironment 12, 47–56 (2019). https://doi.org/10.1007/s12307-019-00224-2

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