論文 - 詳細
| RRC ID | 52326 |
|---|---|
| 著者 | Yoshioka M, Ohashi S, Ida T, Nakai Y, Kikuchi O, Amanuma Y, Matsubara J, Yamada A, Miyamoto S, Natsuizaka M, Nakagawa H, Chiba T, Seno H, Muto M. |
| タイトル | Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells. |
| ジャーナル | J Exp Clin Cancer Res |
| Abstract |
BACKGROUND:Epidermal growth factor receptor (EGFR) plays a pivotal role in the pathophysiology of esophageal squamous cell carcinoma (ESCC). However, the clinical effects of EGFR inhibitors on ESCC are controversial. This study sought to identify the factors determining the therapeutic efficacy of EGFR inhibitors in ESCC cells. METHODS:Immortalized-human esophageal epithelial cells (EPC2-hTERT), transformed-human esophageal epithelial cells (T-Epi and T-Mes), and ESCC cells (TE-1, TE-5, TE-8, TE-11, TE-11R, and HCE4) were treated with the EGFR inhibitors erlotinib or cetuximab. Inhibitory effects on cell growth were assessed by cell counting or cell-cycle analysis. The expression levels of genes and proteins such as involucrin and cytokeratin13 (a squamous differentiation marker), E-cadherin, and vimentin were evaluated by real-time polymerase chain reaction or western blotting. To examine whether mesenchymal phenotype influenced the effects of EGFR inhibitors, we treated T-Epi cells with TGF-β1 to establish a mesenchymal phenotype (mesenchymal T-Epi cells). We then compared the effects of EGFR inhibitors on parental T-Epi cells and mesenchymal T-Epi cells. TE-8 (mesenchymal-like ESCC cells)- or TE-11R (epithelial-like ESCC cells)-derived xenograft tumors in mice were treated with cetuximab, and the antitumor effects of EGFR inhibitors were evaluated. RESULTS:Cells were classified as epithelial-like or mesenchymal-like phenotypes, determined by the expression levels of E-cadherin and vimentin. Both erlotinib and cetuximab reduced cell growth and the ratio of cells in cell-cycle S phase in epithelial-like but not mesenchymal-like cells. Additionally, EGFR inhibitors induced squamous cell differentiation (defined as increased expression of involucrin and cytokeratin13) in epithelial-like but not mesenchymal-like cells. We found that EGFR inhibitors did not suppress the phosphorylation of EGFR in mesenchymal-like cells, while EGFR dephosphorylation was observed after treatment with EGFR inhibitors in epithelial-like cells. Furthermore, mesenchymal T-Epi cells showed resistance to EGFR inhibitors by circumventing the dephosphorylation of EGFR signaling. Cetuximab consistently showed antitumor effects, and increased involucrin expression in TE-11R (epithelial-like)-derived xenograft tumors but not TE-8 (mesenchymal-like)-derived xenograft tumors. CONCLUSIONS:The factor determining the therapeutic effects of EGFR inhibitors in ESCC cells is the phenotype representing the epithelial-like or mesenchymal-like cells. Mesenchymal-like ESCC cells are resistant to EGFR inhibitors because EGFR signaling is not blocked. EGFR inhibitors show antitumor effects on epithelial-like ESCC cells accompanied by promotion of squamous cell differentiation. |
| 巻・号 | 36(1) |
| ページ | 101 |
| 公開日 | 2017-8-1 |
| DOI | 10.1186/s13046-017-0572-7 |
| PII | 10.1186/s13046-017-0572-7 |
| PMID | 28764725 |
| PMC | PMC5540425 |
| MeSH | Animals Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / enzymology Carcinoma, Squamous Cell / pathology Cell Differentiation / drug effects Cell Line, Tumor Cetuximab / pharmacology ErbB Receptors / antagonists & inhibitors* Erlotinib Hydrochloride Esophageal Neoplasms / drug therapy* Esophageal Neoplasms / enzymology Esophageal Neoplasms / pathology Esophageal Squamous Cell Carcinoma Humans Male Mice Mice, Nude Protein Kinase Inhibitors / pharmacology* Signal Transduction Xenograft Model Antitumor Assays |
| IF | 5.646 |
| 引用数 | 13 |
| リソース情報 | |
| ヒト・動物細胞 | TE-1(RCB1894) TE-5(RCB1949) TE-8(RCB2098) TE-11(RCB2100) |