Highlights d Stem cell-derived glioma formation is accompanied by loss of neurogenesis d miR-124-dependent neuronal differentiation reduces glioblastoma (GBM) aggressiveness d An ERK1/2-miR-124-SOX9 axis regulates neuronal differentiation in GBM cells d An miR-124-induced neuronal phenotype sensitizes GBM cells to radiation
Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied by the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models., the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM. .
<p>Fig. S4. AF treatment results in no changes in body weight for mice xenografted with GBM43 cells and resulted in complete tumor regression in an EGFRvIII-expressing GBM allograft model. (A, B) SPC or Salovum treatment had no effect on body weight in GBM43 xenografts (n=7 for control, n=10 for SPC, and n=5 for Salovum). (C) SPC treatment resulted in complete tumor regression in 5/6 FVBn mice allografted with EGFRvIII and mCherry-expressing mouse GBM cells (dotted line; tumor border). Scale bar 2 mm.</p>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.