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Cancer Gene Ther. 2014 Sep;21(9):381-8. doi: 10.1038/cgt.2014.42. Epub 2014 Aug 8.

Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition.

Author information

1
1] Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal University, Bangalore, India [2] Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Perth, Western Australia.
2
Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal University, Bangalore, India.
3
1] Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Perth, Western Australia [2] School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia.
4
School of Surgery, The University of Western Australia, Perth, Western Australia.
5
School of Medicine and Pharmacology, The University of Western Australia, Perth, Western Australia.
6
Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Perth, Western Australia.

Abstract

Cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC) are defined by high self-renewal and drug refractory potential. Involvement of Wnt/β-catenin signaling has been implicated in rapidly cycling cells such as CSCs, and inhibition of the Wnt/β-catenin pathway is a novel approach to target CSCs from HNSCC. In this study, we found that an antagonist of FrzB/Wnt, the secreted frizzled-related protein 4 (sFRP4), inhibited the growth of CSCs from two HNSCC cell lines, Hep2 and KB. We enriched the CD44(+) CSC population, and grew them in spheroid cultures. sFRP4 decreased the proliferation and increased the sensitivity of spheroids to a commonly used drug in HNSCC, namely cisplatin. Self-renewal in sphere formation assays decreased upon sFRP4 treatment, and the effect was reverted by the addition of Wnt3a. sFRP4 treatment of spheroids also decreased β-catenin, confirming its action through the Wnt/β-catenin signaling pathway. Quantitative PCR demonstrated a clear decrease of the stemness markers CD44 and ALDH, and an increase in CD24 and drug-resistance markers ABCG2 and ABCC4. Furthermore, we found that after sFRP4 treatment, there was a reversal in the expression of epithelial to mesenchymal (EMT) markers with the restoration of the epithelial marker E-cadherin, and depletion of EMT-specific markers twist, snail and N-cadherin. This is the first report demonstrating that the naturally occurring Wnt inhibitor, sFRP4, can be a potential drug to destroy CSC-enriched spheroids from HNSCCs. The repression of EMT and the decrease in stemness profile further strengthen the use of sFRP4 as a potent therapeutic against CSCs.

PMID:
25104726
DOI:
10.1038/cgt.2014.42
[Indexed for MEDLINE]
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