PDGF receptor alpha inhibition induces apoptosis in glioblastoma cancer stem cells refractory to anti-Notch and anti-EGFR treatment

Molecular Cancer

Research

Angelo Luigi Vescovi¹  Hany ES Marei²  Armando Felsani³  Emanuela Paldino³  Patrizia Casalbore³  Giulio Maira⁴  Annunziato Mangiola⁴  Carlo Cenciarelli⁵  Manuela Zonfrillo⁵  Pasquale Pierimarchi⁵ 

[1] Department of Biotechnologies and Biosciences, University of Milan-Bicocca, Milan, Italy;Department of Cytology and Histology, Mansoura University, Mansoura, Egypt;Institute of Cell Biology and Neurobiology, Roma, Italy;Institute of Neurosurgery, Catholic University-School of Medicine, Roma, Italy;Institute of Translational Pharmacology-CNR, Roma, Italy;

关键词: Epidermal Growth Factor Receptor;    Cancer Stem Cell;    Epidermal Growth Factor Receptor Inhibition;    Epidermal Growth Factor Receptor Gene;    Epidermal Growth Factor Receptor Signaling;   

DOI  :  10.1186/1476-4598-13-247

 received in 2014-07-03, accepted in 2014-10-27,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundCancer stem cells (CSC) represent a rare fraction of cancer cells characterized by resistance to chemotherapy and radiation, therefore nowadays there is great need to develop new targeted therapies for brain tumors and our study aim to target pivotal transmembrane receptors such as Notch, EGFR and PDGFR, which are already under investigation in clinical trials setting for the treatment of Glioblastoma Multiforme (GBM).MethodsMTS assay was performed to evaluate cells response to pharmacological treatments. Quantitative RT-PCR and Western blots were performed to state the expression of Notch1, EGFR and PDGFRα/β and the biological effects exerted by either single or combined targeted therapy in GBM CSC. GBM CSC invasive ability was tested in vitro in absence or presence of Notch and/or EGFR signaling inhibitors.ResultsIn this study, we investigated gene expression and function of Notch1, EGFR and PDGFR to determine their role among GBM tumor core- (c-CSC) vs. peritumor tissue-derived cancer stem cells (p-CSC) of six cases of GBM. Notch inhibition significantly impaired cell growth of c-CSC compared to p-CSC pools, with no effects observed in cell cycle distribution, apoptosis and cell invasion assays. Instead, anti-EGFR therapy induced cell cycle arrest, sometimes associated with apoptosis and reduction of cell invasiveness in GBM CSC. In two cases, c-CSC pools were more sensitive to simultaneous anti-Notch and anti-EGFR treatment than either therapy alone compared to p-CSC, which were mostly resistant to treatment. We reported the overexpression of PDGFRα and its up-regulation following anti-EGFR therapy in GBM p-CSC compared to c-CSC. RNA interference of PDGFRα significantly reduced cell proliferation rate of p-CSC, while its pharmacological inhibition with Crenolanib impaired survival of both CSC pools, whose effects in combination with EGFR inhibition were maximized.ConclusionsWe have used different drugs combination to identify the more effective therapeutic targets for GBM CSC, particularly against GBM peritumor tissue-derived CSC, which are mostly resistant to treatments. Overall, our results provide the rationale for simultaneous targeting of EGFR and PDGFR, which would be beneficial in the treatment of GBM.

【 授权许可】

CC BY   
© Cenciarelli et al.; licensee BioMed Central Ltd. 2014