title: Cancer stem-like cell properties are regulated by EGFR/AKT/β-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma.
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.
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Lei
authors: L
authors: Ma
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Gong
authors: G
authors: Zhang
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Xiao-Bo
authors: XB
authors: Miao
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Xu-Bin
authors: XB
authors: Deng
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Yue
authors: Y
authors: Wu
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Ying
authors: Y
authors: Liu
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Zhi-Ru
authors: ZR
authors: Jin
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Xi-Qing
authors: XQ
authors: Li
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Qiu-Zhen
authors: QZ
authors: Liu
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors: Du-Xin
authors: DX
authors: Sun
authors: Fox Chase Cancer Center, Philadelphia, USA.
authors: Joseph R
authors: JR
authors: Testa
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Kai-Tai
authors: KT
authors: Yao
authors: Cancer Institute, Southern Medical University, Guangzhou, China.
authors: Guang-Hui
authors: GH
authors: Xiao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D011799:Quinazolines; D051176:beta Catenin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin; D000077156:Gefitinib