Targeting Cancer Stem Cell Plasticity Through Modulation of Epidermal Growth Factor and Insulin-Like Growth Factor Receptor Signaling in Head and Neck Squamous Cell Cancer. (14th July 2014)

• Record Type: Journal Article
• Authors: Leong, Hui Sun; Chong, Fui Teen; Sew, Pui Hoon; Lau, Dawn P.; Wong, Bernice H.; Teh, Bin-Tean; Tan, Daniel S.W.; Iyer, N. Gopalakrishna
• Is Part Of: Stem cells translational medicine. Volume 3:Number 9(2014)
• Page Start: 1055
• Page End: 1065
• Publication Date: 2014-07-14
• Subjects: Epidermal growth factor receptor -- Insulin-like growth factor-1 receptor -- Aldehyde dehydrogenase -- Head and neck squamous cell cancer -- Cancer stem cell; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.5966/sctm.2013-0214
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract : An in vitro system that recapitulates stem cell plasticity in head and neck squamous cell cancers (HNSCCs) was established and the factors that play a role in the maintenance and repopulation of cancer stem cells (CSCs) were identified. The results show that HNSCC CSCs exhibit plasticity, with maintenance of the stem cell fraction dependent on the epidermal growth factor receptor and insulin-like growth factor-1 receptor pathways and potentially amenable to targeted therapeutics. Abstract: : Emerging data suggest that cancer stem cells (CSCs) exist in equilibrium with differentiated cells and that stochastic transitions between these states can account for tumor heterogeneity and drug resistance. The aim of this study was to establish an in vitro system that recapitulates stem cell plasticity in head and neck squamous cell cancers (HNSCCs) and identify the factors that play a role in the maintenance and repopulation of CSCs. Tumor spheres were established using patient-derived cell lines via anchorage-independent cell culture techniques. These tumor spheres were found to have higher aldehyde dehydrogenase (ALD) cell fractions and increased expression of Kruppel-like factor 4, SRY (sex determining region Y)-box 2, and Nanog and were resistant to γ-radiation, 5-fluorouracil, cisplatin, and etoposide treatment compared with monolayer culture cells. Monolayer cultures were subject to single cell cloning to generate clones with high and low ALD fractions. ALD High clones showed higher expression of stem cell and epithelial-mesenchymal transition markers compared with ALD Low clones. ALD fractions, representing stem cell fractions, fluctuated with serial passaging, equilibrating at a level specific to each cell line, and could be augmented by the addition of epidermal growth factor (EGF) and/or insulin. ALD High clones showed increased EGF receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) phosphorylation, with increased activation of downstream pathways compared with ALD Low clones. Importantly, blocking these pathways using specific inhibitors against EGFR and IGF-1R reduced stem cell fractions drastically. Taken together, these results show that HNSCC CSCs exhibit plasticity, with the maintenance of the stem cell fraction dependent on the EGFR and IGF-1R pathways and potentially amenable to targeted therapeutics.