title: EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition.
abstract: There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF-β in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-β1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC.
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sato
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kubota
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuizaka
authors.forename: Osamu
authors.initials: O
authors.lastname: Maehara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatanaka
authors.forename: Katsuji
authors.initials: K
authors.lastname: Marukawa
authors.forename: Katsumi
authors.initials: K
authors.lastname: Terashita
authors.forename: Goki
authors.initials: G
authors.lastname: Suda
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohashi
authors.forename: Shingo
authors.initials: S
authors.lastname: Kagawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kinugasa
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Whelan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
keywords: CK13, cytokeratin 13; CSCs, cancer stem-like cells; DMSO, dimethyl sulfoxide; EMT, epithelial–mesenchymal transition; EGFR, epidermal growth factor receptor; ESCC, esophageal squamous cell carcinoma; FACS, fluorescence-activated cell sorting; IHC, immun; EGFR inhibitor; ZEB1; cancer stem cell; epithelial-mesenchymal transition; esophageal squamous cell carcinoma; organotypic 3D culture