Abstract
BackgroundGlioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs’ alteration remain unkown.MethodsWe collected EVs in the culture medium of three classic glioblastoma cell lines, U87 and A172 (male cell lines), and LN229 (female cell line). U87, A172, and LN229 were co-cultured with their corresponding EVs, respectively. Mouse NPCs (mNPCs) were co-cultured with glioblastoma-derived EVs. The proliferation and migration of tumor cells and mNPCs after EVs treatment were examined. Proteomic analysis and western blotting were utilized to identify the underlying mechanisms of glioblastoma-derived EVs-induced alterations in mNPCs.ResultsWe first show that glioblastoma cell lines U87-, A172-, and LN229-derived EVs were essential for glioblastoma cell prolifeartion and migration. We then demonstrated that glioblastoma-derived EVs dramatically promoted NPC proliferation and migration. Mechanistic studies identify that glioblastoma-derived EVs achieve their functions via activating PI3K-Akt-mTOR pathway in mNPCs. Inhibiting PI3K-Akt pathway reversed the elevated prolfieration and migration of glioblastoma-derived EVs-treated mNPCs.ConclusionOur findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy.9isrUz1Ju_9yzYdEacJBzAVideo
Highlights
Glioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies
Nanoparticle tracking analysis (NTA) analyses demonstrated similar sizes for extracellular vesicles (EVs) released from U87 (Additional file 1: Fig. S1A), A172 (Additional file 1: Fig. S1B), and LN229 (Additional file 1: Fig. S1C), suggesting there was no significant difference in size distributions of different types of EVs
We examined the proliferation of Mouse Neural progenitor cells (NPCs) (mNPCs) treated with either U87-derived EVs (U87-EVs), A172-EVs, or LN229-EVs with EdU, Ki67, and CCK8 assays
Summary
Glioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Glioblastomas are known to have the capacity to recruit and alter the phenotypes of normal cells in their environs to sustain growth and encroachment into other regions [7]. Numerous forms of cell–cell communication are utilized by glioblastomas to “hijack” cells in the TME to promote tumor progression [3,4,5] These routes include direct secretion of soluble factors, exchange of proteins and molecules via gap junctions, and transfer cellular contents via extracellular vesicles (EVs) [8]. Through these routes, glioblastomas alter immune cell function, sustain tumor vasculature, cause neurotoxicity, and alter astroglia phenotypes. A dominant proportion of surrounding cells further provide feedback to potentiate glioblastoma aggressiveness via this crosstalk [9, 10]
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