Differentiation therapy exerts antitumor effects on stem-like glioma cells

Benito Campos, Feng Wan, Mohammad Farhadi, Aurélie Ernst, Felix Zeppernick, Katrin E Tagscherer, Rezvan Ahmadi, Jennifer Lohr, Christine Dictus, Georg Gdynia, Stephanie E Combs, Violaine Goidts, Burkhard M Helmke, Volker Eckstein, Wilfried Roth, Philipp Beckhove, Peter Lichter, Andreas Unterberg, Bernhard Radlwimmer, Christel Herold-Mende
Clinical Cancer Research 2010 May 15, 16 (10): 2715-28

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

RESULTS: 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.

CONCLUSIONS: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma.

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