EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition
| Autor: | Hiroshi Nakagawa, Fumiyuki Sato, Kelly A. Whelan, Shinya Ohashi, Yoshimasa Kubota, Yuichi Shimizu, Katsumi Terashita, Osamu Maehara, Yutaka Hatanaka, Goki Suda, Hideaki Kinugasa, Mitsuteru Natsuizaka, Naoya Sakamoto, Yoshito Komatsu, Shingo Kagawa, Katsuji Marukawa, Shunsuke Ohnishi |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Epithelial-Mesenchymal Transition Esophageal Neoplasms Cellular differentiation Erlotinib Hydrochloride Cancer stem cell Cell Line Tumor Spheroids Cellular Internal medicine Tumor Cells Cultured medicine Humans Epithelial–mesenchymal transition neoplasms Cell Proliferation EGFR inhibitors Homeodomain Proteins Pharmacology biology Cetuximab CD44 Zinc Finger E-box-Binding Homeobox 1 digestive system diseases Tumor Burden ErbB Receptors Drug Resistance Neoplasm embryonic structures Carcinoma Squamous Cell Neoplastic Stem Cells biology.protein Molecular Medicine Esophageal Squamous Cell Carcinoma Erlotinib Transcription Factors Research Paper medicine.drug |
| Zdroj: | Cancer Biology & Therapy. 16:933-940 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.1080/15384047.2015.1040959 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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