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Targeting osteopontin suppresses glioblastoma stem‐like cell character and tumorigenicity in vivo
Author(s) -
Lamour Virginie,
Henry Aurélie,
Kroonen Jérôme,
Nokin MarieJulie,
von Marschall Zofia,
Fisher Larry W.,
Chau TieuLan,
Chariot Alain,
Sanson Marc,
Delattre JeanYves,
Turtoi Andrei,
Peulen Olivier,
Rogister Bernard,
Castronovo Vincent,
Bellahcène Akeila
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29454
Subject(s) - osteopontin , cd44 , cancer research , gene silencing , homeobox protein nanog , sox2 , biology , autocrine signalling , stem cell , glioma , tumor progression , carcinogenesis , pi3k/akt/mtor pathway , cell growth , tumor initiation , cell culture , signal transduction , cell , immunology , transcription factor , cancer , microbiology and biotechnology , induced pluripotent stem cell , embryonic stem cell , biochemistry , genetics , gene
Osteopontin (OPN) is a secreted protein involved in most aspects of tumor progression and metastasis development. Elevated OPN expression has been reported in multiple types of cancer including glioblastoma (GBM), the highest grade and most aggressive brain tumor. GBMs contain a subpopulation of glioma‐initiating cells (GICs) implicated in progression, therapeutic resistance and recurrence. We have previously demonstrated that OPN silencing inhibited GBM cell growth in vitro and in vivo . Moreover, activation of CD44 signaling upon OPN ligation has been recently implicated in the acquisition of a stem cell phenotype by GBM cells. The present study is aimed to explore OPN autocrine function using shRNA silencing strategy in GICs enriched from GBM cell lines and a human primary GBM grown in EGF and bFGF defined medium. The removal of these growth factors and addition of serum induced a significant loss of OPN expression in GICs. We showed that OPN‐silenced GICs were unable to grow as spheres and this capacity was restored by exogenous OPN. Importantly, the expression of Sox2, Oct3/4 and Nanog, key stemness transcription factors, was significantly decreased in GICs upon OPN targeting. We identified Akt/mTOR/p70S6K as the main signaling pathway triggered following OPN‐mediated EGFR activation in GICs. Finally, in an orthotopic xenograft mouse model, the tumorigenic potential of U87‐MG sphere cells was completely abrogated upon OPN silencing. Our demonstration of endogenous OPN major regulatory effects on GICs stemness phenotype and tumorigenicity implies a greater role than anticipated for OPN in GBM pathogenesis from initiation and progression to probable recurrence.