It appears you don't have support to open PDFs in this web browser. To view this file, Open with your PDF reader
Abstract
Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial–mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Philadelphia, PA, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
2 Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Philadelphia, PA, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
3 Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Philadelphia, PA, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
4 Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Philadelphia, PA, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Surgery, Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
5 Abramson Cancer Center, Philadelphia, PA, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA, USA
6 Department of Oral Immunology and Infectious Diseases, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA
7 Department of Medicine, Division of Digestive and Liver Diseases, Columbia University, New York, NY, USA
8 Abramson Cancer Center, Philadelphia, PA, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
9 Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
10 Department of Pathology, Kochi Medical School, Nankoku-shi, Kochi, Japan
11 Histopathology Facility and Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
12 Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
13 Dana–Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA
14 Dana–Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Hematology and Medical Oncology, New York University, New York, NY, USA
15 University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA