The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cellsReport as inadecuate




The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells - Download this document for free, or read online. Document in PDF available to download.

Stem Cell Research and Therapy

, 8:119

First Online: 25 May 2017Received: 24 January 2017Revised: 31 March 2017Accepted: 04 May 2017DOI: 10.1186-s13287-017-0573-7

Cite this article as: Pattarozzi, A., Carra, E., Favoni, R.E. et al. Stem Cell Res Ther 2017 8: 119. doi:10.1186-s13287-017-0573-7

Abstract

BackgroundMalignant pleural mesothelioma is an aggressive cancer, characterized by rapid progression and high mortality. Persistence of tumor-initiating cells TICs, or cancer stem cells after cytotoxic drug treatment is responsible for tumor relapse, and represents one of the main reasons for the poor prognosis of mesothelioma. In fact, identification of the molecules affecting TIC viability is still a significant challenge.

MethodsTIC-enriched cultures were obtained from 10 human malignant pleural mesotheliomas and cultured in vitro. Three fully characterized tumorigenic cultures, named MM1, MM3, and MM4, were selected and used to assess antiproliferative effects of the multi-kinase inhibitor sorafenib. Cell viability was investigated by MTT assay, and cell cycle analysis as well as induction of apoptosis were determined by flow cytometry. Western blotting was performed to reveal the modulation of protein expression and the phosphorylation status of pathways associated with sorafenib treatment.

ResultsWe analyzed the molecular mechanisms of the antiproliferative effects of sorafenib in mesothelioma TIC cultures. Sorafenib inhibited cell cycle progression in all cultures, but only in MM3 and MM4 cells was this effect associated with Mcl-1-dependent apoptosis. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with epidermal growth factor EGF or basic fibroblast growth factor bFGF causing, in MM3 and MM4 cells, MEK, ERK1-2, Akt, and STAT3 phosphorylation. These effects were abolished by sorafenib only in bFGF-treated cells, while a modest inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGF receptor FGFR inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib.

Moreover, in MM1 cells, which release high levels of bFGF and showed autocrine activation of FGFR1 and constitutive phosphorylation-activation of MEK-ERK1-2, sorafenib induced a more effective antiproliferative response, confirming that the main target of the drug is the inhibition of FGFR1 activity.

ConclusionsThese results suggest that, in malignant pleural mesothelioma TICs, bFGF signaling is the main target of the antiproliferative response of sorafenib, acting directly on the FGFR1 activation. Patients with constitutive FGFR1 activation via an autocrine loop may be more sensitive to sorafenib treatment and the analysis of this possibility warrants further clinical investigation.

KeywordsPleural mesothelioma Tumor-initiating cells Sorafenib Fibroblast growth factor Apoptosis AbbreviationsbFGFBasic fibroblast growth factor

CSCCancer stem cell

EGFEpidermal growth factor

MPMMalignant pleural mesothelioma

TICTumor-initiating cell

TKITyrosine kinase inhibitor

Electronic supplementary materialThe online version of this article doi:10.1186-s13287-017-0573-7 contains supplementary material, which is available to authorized users.





Author: Alessandra Pattarozzi - Elisa Carra - Roberto E. Favoni - Roberto Würth - Daniela Marubbi - Rosa Angela Filiberti - Lucia

Source: https://link.springer.com/







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