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

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.

Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

“…As a result, 23 inhibitors from different families showed significant anticancer effect in at least two cell lines (figure 1A, see online supplementary table S1). Many of the kinase inhibitors previously shown to have anti-OSCC properties in vitro, including those targeting PI3K/AKT/MTOR pathway,19 20 HSP family21 22 or RTK,23 24 also demonstrated potent activities here, validating the methodology of our high-throughput approach (see online supplementary figure S1). As CDK inhibitors have shown promising therapeutic merit in several other types of tumours but are less well-studied in OSCC, we focused on this category of chemicals.…”

Association between periostin and epithelial-mesenchymal transition in esophageal squamous cell carcinoma and its clinical significance

“…EMT has been demonstrated to be involved in several underlying mechanisms leading to tumor invasion, migration and the induction of cancer stem-like cells in esophageal cancer (19,20). In the present study, expression levels of E-cad and Vim in ESCC squamous cells changed abnormally and inversely.…”

TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

“…Recent research has revealed the correlation between cancer stemness and epithelial-mesenchymal transition [42,43]. In this study we showed that transient knockdown of TDO2 by RNAi reduced activation of the EGFR signaling pathway and reduced spheroid formation in ESCC cell lines, although the epithelial-mesenchymal transition profiles were not examined.…”

“…Interestingly, a previous study reported that inhibition of EGFR could prevent the induction of cancer stem-like cells in ESCC through suppressing epithelialmesenchymal transition [42]. Recent research has revealed the correlation between cancer stemness and epithelial-mesenchymal transition [42,43].…”