Clinical cancer research, 2010-05-15, Vol.16 (10), p.2715-2728
Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications.
Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model.
Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo.
Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma.
Immunohistochemistry ; Cell Separation ; Neoplastic Stem Cells - drug effects ; Humans ; Brain Neoplasms - pathology ; In Situ Hybridization, Fluorescence ; Brain Neoplasms - drug therapy ; Blotting, Western ; Xenograft Model Antitumor Assays ; Animals ; Flow Cytometry ; Cell Differentiation - drug effects ; Glioma - pathology ; Polymerase Chain Reaction ; Neoplastic Stem Cells - pathology ; Mice, Inbred NOD ; Antineoplastic Agents - pharmacology ; Mice ; Glioma - drug therapy ; Tretinoin - pharmacology
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