Yu Fang1,2, Wenbo Li3,2, Xiaoxin Chen4. 1. Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400045, China. 2. Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George St, Durham, NC, 27707, USA. 3. Department of Gastroenterology, Clinical Teaching Hospital of JinZhou Medical University, 960 Hospital, Jinan, 250031, China. 4. Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George St, Durham, NC, 27707, USA. lchen@nccu.edu.
Abstract
BACKGROUND: The cellular origin and molecular mechanisms of Barrett's esophagus (BE) are still controversial. Trans-differentiation is a mechanism characterized by activation of the intestinal differentiation program and inactivation of the squamous differentiation program. AIMS: Renal capsule grafting (RCG) was used to elucidate whether CDX2 overexpression on the basis of P63 deficiency in the esophageal epithelium may generate intestinal metaplasia. METHODS: P63-/-;Villin-Cdx2 embryos were generated by crossing P63+/- mice with Villin-Cdx2 mice. E18.5 esophagus was xenografted in a renal capsule grafting (RCG) model. At 1, 2, or 4 weeks after RCG, the mouse esophagus was immunostained for a proliferation marker (BrdU), squamous transcription factors (SOX2, PAX9), squamous differentiation markers (CK5, CK4, and CK1), intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6), intestinal columnar epithelial cell markers (A33, CK8), goblet cell marker (MUC2, TFF3), Paneth cell markers (LYZ and SOX9), enteroendocrine cell marker (CHA), and Tuft cell marker (DCAMKL1). RESULTS: The P63-/-;Villin-Cdx2 RCG esophagus was lined with proliferating PAS/AB+ cuboidal cells and formed an intestinal crypt-like structure. The goblet cell markers (TFF3 and MUC2) and intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6) were expressed although no typical morphology of goblet cells was observed. Other intestinal cell markers including enteroendocrine cell marker (CHA), Paneth cell markers (LYZ and Sox9), and intestinal secretory cell marker (UEA/WGA) were also expressed in the P63-/-;Villin-Cdx2 RCG esophagus. Squamous cell markers (PAX9 and SOX2) were also expressed, suggesting a transitional phenotype. CONCLUSION: CDX2 overexpression on the basis of P63 deficiency in esophageal epithelial cells induces Barrett's-like metaplasia in vivo. Additional factors may be needed to drive this transitional phenotype into full-blown BE.
BACKGROUND: The cellular origin and molecular mechanisms of Barrett's esophagus (BE) are still controversial. Trans-differentiation is a mechanism characterized by activation of the intestinal differentiation program and inactivation of the squamous differentiation program. AIMS: Renal capsule grafting (RCG) was used to elucidate whether CDX2 overexpression on the basis of P63 deficiency in the esophageal epithelium may generate intestinal metaplasia. METHODS: P63-/-;Villin-Cdx2 embryos were generated by crossing P63+/- mice with Villin-Cdx2 mice. E18.5 esophagus was xenografted in a renal capsule grafting (RCG) model. At 1, 2, or 4 weeks after RCG, the mouse esophagus was immunostained for a proliferation marker (BrdU), squamous transcription factors (SOX2, PAX9), squamous differentiation markers (CK5, CK4, and CK1), intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6), intestinal columnar epithelial cell markers (A33, CK8), goblet cell marker (MUC2, TFF3), Paneth cell markers (LYZ and SOX9), enteroendocrine cell marker (CHA), and Tuft cell marker (DCAMKL1). RESULTS: The P63-/-;Villin-Cdx2 RCG esophagus was lined with proliferating PAS/AB+ cuboidal cells and formed an intestinal crypt-like structure. The goblet cell markers (TFF3 and MUC2) and intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6) were expressed although no typical morphology of goblet cells was observed. Other intestinal cell markers including enteroendocrine cell marker (CHA), Paneth cell markers (LYZ and Sox9), and intestinal secretory cell marker (UEA/WGA) were also expressed in the P63-/-;Villin-Cdx2 RCG esophagus. Squamous cell markers (PAX9 and SOX2) were also expressed, suggesting a transitional phenotype. CONCLUSION: CDX2 overexpression on the basis of P63 deficiency in esophageal epithelial cells induces Barrett's-like metaplasia in vivo. Additional factors may be needed to drive this transitional phenotype into full-blown BE.
Authors: A Yang; R Schweitzer; D Sun; M Kaghad; N Walker; R T Bronson; C Tabin; A Sharpe; D Caput; C Crum; F McKeon Journal: Nature Date: 1999-04-22 Impact factor: 49.962
Authors: Bashar J Qumseya; Yazan Qumsiyeh; Sandeep A Ponniah; David Estores; Dennis Yang; Crystal N Johnson-Mann; Jeffrey Friedman; Alexander Ayzengart; Peter V Draganov Journal: Gastrointest Endosc Date: 2020-08-14 Impact factor: 9.427