Joline S Hartheimer, Seungjo Park, Shreyas S Rao, Yonghyun Kim
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Targeting Hyaluronan Interactions for Glioblastoma Stem Cell Therapy.
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.
期刊介绍：
Cancer Microenvironment is the official journal of the International Cancer Microenvironment Society (ICMS). It publishes original studies in all aspects of basic, clinical and translational research devoted to the study of cancer microenvironment. It also features reports on clinical trials.
Coverage in Cancer Microenvironment includes: regulation of gene expression in the cancer microenvironment; innate and adaptive immunity in the cancer microenvironment, inflammation and cancer; tumor-associated stroma and extracellular matrix, tumor-endothelium interactions (angiogenesis, extravasation), cancer stem cells, the metastatic niche, targeting the tumor microenvironment: preclinical and clinical trials.
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