Abstract
We report that the epidermal growth factor receptor (EGFR) pathway plays a critical role in regulating cancer stem-like cells (CSCs) in nasopharyngeal carcinoma (NPC), one of the most common malignant tumors in Southeast Asia. Effects of EGFR on maintaining CSCs are mainly mediated by AKT signaling, and β-catenin is responsible for governing CSC properties in response to EGFR/AKT activation. Significantly, CSCs are enriched by cisplatin and decreased by gefitinib in NPC xenograft models. Upon reimplantation in secondary mice, tumor cells derived from cisplatin-treated mice grew rapidly, whereas regrowth of tumor cells from gefitinib-treated mice was severely diminished. We further demonstrate that expression of EGFR correlates with expression of β-catenin and Nanog in primary tumor specimens from NPC patients. These findings provide mechanistic and preclinical evidence supporting the use of gefitinib alone or in combination with a chemotherapeutic agent in first-line therapy for patients with NPC. In addition, our results suggest that targeting β-catenin represents a rational clinical modality for patients whose tumors harbor activated EGFR or AKT.
© 2013 The Authors Journal compilation © 2013 FEBS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Carcinoma / drug therapy
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Carcinoma / metabolism
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Carcinoma / pathology*
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival / drug effects
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Cell Transformation, Neoplastic / metabolism
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Cisplatin / pharmacology
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Gefitinib
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Gene Knockdown Techniques
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Homeodomain Proteins / metabolism
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nanog Homeobox Protein
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Nasopharyngeal Carcinoma
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Nasopharyngeal Neoplasms / drug therapy
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / pathology*
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Neoplasm Transplantation
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology*
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Side-Population Cells / drug effects
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Side-Population Cells / metabolism
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Signal Transduction*
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Spheroids, Cellular / metabolism
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Spheroids, Cellular / physiology
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Xenograft Model Antitumor Assays
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Antineoplastic Agents
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Homeodomain Proteins
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NANOG protein, human
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Nanog Homeobox Protein
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Quinazolines
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beta Catenin
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Cisplatin
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Gefitinib