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 utilized two classic glioblastoma cell lines, U87- and A172, and collected EVs in the culture medium of those two lines. Mouse NPCs (mNPCs) were co-cultured with U87- or A172-derived EVs. EVs-treated mNPCs’ prolifeartion and migration were examined. Proteomic analysis and western-blot were utilized to identify the underlying mechanisms of glioblastoma EVs-induced alterations in mNPCs.ResultsWe show that glioblastoma cell lines U87- and A172-derived EVs dramatically promoted NPCs proliferation and migration. Mechanistic studies identify that EVs achieve their functions via activating PI3K-Akt-mTOR pathway in recipient cells. Inhibiting PI3K-Akt reversed the elevated prolfieration and migration of glioblastoma 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.
Sphingosine-1-Phosphate Receptor Antagonism Enhances Proliferation and Migration of Engrafted Neural Progenitor Cells in a Model of Viral-Induced Demyelination