Osteopontin-CD44 Signaling in the Glioma Perivascular Niche Enhances Cancer Stem Cell Phenotypes and Promotes Aggressive Tumor Growth
Menée à l'aide d'un modèle murin de gliome, cette étude met en évidence des mécanismes par lesquels, en s'exprimant dans la niche périvasculaire de la tumeur, l'ostéopontine active la signalisation CD44, ce qui favorise la prolifération des cellules souches de gliomes ainsi que la résistance à une radiothérapie
Stem-like glioma cells reside within a perivascular niche and display hallmark radiation resistance. An understanding of the mechanisms underlying these properties will be vital for the development of effective therapies. Here, we show that the stem cell marker CD44 promotes cancer stem cell phenotypes and radiation resistance. In a mouse model of glioma, Cd44−/− and Cd44+/− animals showed improved survival compared to controls. The CD44 ligand osteopontin shared a perivascular expression pattern with CD44 and promoted glioma stem cell-like phenotypes. These effects were mediated via the
γ-secretase-regulated intracellular domain of CD44, which promoted aggressive glioma growth in vivo and stem cell-like phenotypes via CBP/p300-dependent enhancement of HIF-2α activity. In human glioblastoma multiforme, expression of CD44 correlated with hypoxia-induced gene signatures and poor survival. Altogether, these data suggest that in the glioma perivascular niche, osteopontin promotes stem cell-like properties and radiation resistance in adjacent tumor cells via activation of CD44 signaling.
"CD44 promotes aggressive glioma growth and cancer stem cell phenotypes "Osteopontin-CD44 signaling induces stemness and radiation resistance "The CD44 intracellular domain is sufficient to promote glioma growth "CD44ICD regulates HIF-2
α via CBP/p300 to drive stemness and radiation resistance
Pietras et al. show osteopontin is expressed in the glioma perivascular niche and activates CD44 signaling, which drives tumor growth and promotes glioma stem cell phenotypes via CBP/p300-mediated enhancement of
HIF-2α
http://linkinghub.elsevier.com/retrieve/pii/S193459091400006X