Cancer stem-like cell properties are regulated by EGFR/AKT/β-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma

FEBS J. 2013 May;280(9):2027-41. doi: 10.1111/febs.12226. Epub 2013 Apr 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma / drug therapy
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cisplatin / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Gefitinib
  • Gene Knockdown Techniques
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanog Homeobox Protein
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / drug therapy
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology*
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinazolines / pharmacology*
  • Side-Population Cells / drug effects
  • Side-Population Cells / metabolism
  • Signal Transduction*
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / physiology
  • Xenograft Model Antitumor Assays
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Quinazolines
  • beta Catenin
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Cisplatin
  • Gefitinib