In this review, we explore a paligenosis-based model to explain Barrett's esophagus development and progression: ‘the cyclical hit model.’
Genomic analyses have highlighted the high mutational burden of esophageal adenocarcinoma, Barrett's esophagus, and even normal esophageal epithelium. Somatic mutations in key genes including TP53 occur early in the neoplastic progression sequence of Barrett's esophagus, whereas chromosomal amplification resulting in oncogene activation occurs as a critical late event. Paligenosis is a shared injury response mechanism characterized by activation of autophagy, expression of progenitor markers, and increased mTORC signaling-induced cell-cycle reentry. In the setting of chronic injury/inflammation, cycles of paligenosis may allow accumulation of mutations until eventually the mutational burden, in concert perhaps with mutations in key driver oncogenes, finally alters the cell's ability to redifferentiate, leading to the emergence of a potential neoplastic clone.
Under conditions of chronic gastroesophageal refluxate exposure, the normal esophageal squamous epithelium might undergo multiple cycles of paligenosis, allowing initially silent mutations to accumulate until key events impart mutant clones with an oncogenic survival advantage.
aDivision of Oncology
bDivision of Gastroenterology, Department of Internal Medicine
cDepartment of Developmental Biology
dDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
Correspondence to Jason C. Mills, Washington University School of Medicine, St. Louis, MO, USA. Tel: +1 314 362 4213; fax: +1 314 362 7487; e-mail: firstname.lastname@example.org