EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition

Fumiyuki Sato, Yoshimasa Kubota, Mitsuteru Natsuizaka, Osamu Maehara, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Goki Suda, Shunsuke Ohnishi, Yuichi Shimizu, Yoshito Komatsu, Shinya Ohashi, Shingo Kagawa, Hideaki Kunugasa, Kelly A. Whelan, Hiroshi Nakagawa, Naoya Sakamoto

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)933-940
Number of pages8
JournalCancer Biology and Therapy
Volume16
Issue number6
DOIs
Publication statusPublished - Jan 1 2015

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Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Esophageal Squamous Cell Carcinoma
Stem Cell Niche
Human Engineering
Tissue Engineering
Cell Differentiation
Therapeutics
Epithelial Cells

Keywords

  • Cancer stem cell
  • EGFR inhibitor
  • Epithelial-mesenchymal transition
  • Esophageal squamous cell carcinoma
  • Organotypic

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition. / Sato, Fumiyuki; Kubota, Yoshimasa; Natsuizaka, Mitsuteru; Maehara, Osamu; Hatanaka, Yutaka; Marukawa, Katsuji; Terashita, Katsumi; Suda, Goki; Ohnishi, Shunsuke; Shimizu, Yuichi; Komatsu, Yoshito; Ohashi, Shinya; Kagawa, Shingo; Kunugasa, Hideaki; Whelan, Kelly A.; Nakagawa, Hiroshi; Sakamoto, Naoya.

In: Cancer Biology and Therapy, Vol. 16, No. 6, 01.01.2015, p. 933-940.

Research output: Contribution to journalArticle

Sato, F, Kubota, Y, Natsuizaka, M, Maehara, O, Hatanaka, Y, Marukawa, K, Terashita, K, Suda, G, Ohnishi, S, Shimizu, Y, Komatsu, Y, Ohashi, S, Kagawa, S, Kunugasa, H, Whelan, KA, Nakagawa, H & Sakamoto, N 2015, 'EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition', Cancer Biology and Therapy, vol. 16, no. 6, pp. 933-940. https://doi.org/10.1080/15384047.2015.1040959
Sato, Fumiyuki ; Kubota, Yoshimasa ; Natsuizaka, Mitsuteru ; Maehara, Osamu ; Hatanaka, Yutaka ; Marukawa, Katsuji ; Terashita, Katsumi ; Suda, Goki ; Ohnishi, Shunsuke ; Shimizu, Yuichi ; Komatsu, Yoshito ; Ohashi, Shinya ; Kagawa, Shingo ; Kunugasa, Hideaki ; Whelan, Kelly A. ; Nakagawa, Hiroshi ; Sakamoto, Naoya. / EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition. In: Cancer Biology and Therapy. 2015 ; Vol. 16, No. 6. pp. 933-940.
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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.",
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AU - Kagawa, Shingo

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