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 language | English |
|---|---|
| Pages (from-to) | 933-940 |
| Number of pages | 8 |
| Journal | Cancer Biology and Therapy |
| Volume | 16 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jan 1 2015 |
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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 journal › Article
}
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 - Kunugasa, Hideaki
AU - Whelan, Kelly A.
AU - Nakagawa, Hiroshi
AU - Sakamoto, Naoya
PY - 2015/1/1
Y1 - 2015/1/1
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 - Cancer stem cell
KW - EGFR inhibitor
KW - Epithelial-mesenchymal transition
KW - Esophageal squamous cell carcinoma
KW - Organotypic
UR - http://www.scopus.com/inward/record.url?scp=84943758352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943758352&partnerID=8YFLogxK
U2 - 10.1080/15384047.2015.1040959
DO - 10.1080/15384047.2015.1040959
M3 - Article
C2 - 25897987
AN - SCOPUS:84943758352
VL - 16
SP - 933
EP - 940
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 6
ER -