TY - JOUR
T1 - EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition
AU - Sato, Fumiyuki
AU - Kubota, Yoshimasa
AU - Natsuizaka, Mitsuteru
AU - Maehara, Osamu
AU - Hatanaka, Yutaka
AU - Marukawa, Katsuji
AU - Terashita, Katsumi
AU - Suda, Goki
AU - Ohnishi, Shunsuke
AU - Shimizu, Yuichi
AU - Komatsu, Yoshito
AU - Ohashi, Shinya
AU - Kagawa, Shingo
AU - Kinugasa, Hideaki
AU - Whelan, Kelly A
AU - Nakagawa, Hiroshi
AU - Sakamoto, Naoya
N1 - Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Carcinoma, Squamous Cell/metabolism
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Drug Resistance, Neoplasm
KW - Epithelial-Mesenchymal Transition/drug effects
KW - ErbB Receptors/antagonists & inhibitors
KW - Erlotinib Hydrochloride/pharmacology
KW - Esophageal Neoplasms/metabolism
KW - Esophageal Squamous Cell Carcinoma
KW - Homeodomain Proteins/metabolism
KW - Humans
KW - Neoplastic Stem Cells/drug effects
KW - Spheroids, Cellular
KW - Transcription Factors/metabolism
KW - Tumor Burden
KW - Tumor Cells, Cultured
KW - Zinc Finger E-box-Binding Homeobox 1
UR - http://www.scopus.com/inward/record.url?scp=84943758352&partnerID=8YFLogxK
U2 - 10.1080/15384047.2015.1040959
DO - 10.1080/15384047.2015.1040959
M3 - Article
C2 - 25897987
SN - 1538-4047
VL - 16
SP - 933
EP - 940
JO - Cancer Biology & Therapy
JF - Cancer Biology & Therapy
IS - 6
ER -