Abstract
Abstract There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44 (CD44H). CD44H cells have cancer stem-like characteristics and as few as ten CD44H cells can form tumors in an athymic nude mouse. Epithelial-mesenchymal transition (EMT) has a critical role to maintain CD44H cells in ESCC. Notch1-mediated signaling may facilitate either EMT or squamous-cell differentiation in a context-dependent manner. However, detailed mechanism how Notch signaling promotes either EMT or differentiation remains unclear. We investigated how TGF-β in tumor microenvironment might influence Notch signaling to maintain CD44H cells via EMT in ESCC. TGF-β promoted EMT and enriched CD44H cells by activating Notch1 and ZEB1 and suppressing Notch3, while in absence of TGF-β, Notch1 rather activated Notch3, one of pivotal transcription factors in keratinocyte differentiation, led to keratinocyte differentiation. Highly conserved binding sites of ZEB1 exist in the 2nd intron of Notch3. ZEB1 induced by TGF-β bound to the 2nd intron of Notch3 and sharply suppressed the Notch3 transcription, confirmed by CHIP and luciferase assay. Thus TGF-β and Notch1 cooperatively promote EMT and maintain tumor initiating cells. TGF-β signaling influences the tumor initiating capacity of ESCC by modulating novel opposing activities of Notch1 and Notch3 in EMT, and may have translational implications. Citation Format: Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa. TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A74. doi:10.1158/1538-7445.CHTME14-A74
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