Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker

Abstract

Barrett’s esophagus (BE) is a precursor of the esophageal adenocarcinoma (EAC). BE- development and its progression to cancer is associated with gastroesophageal reflux disease. However, there is currently no molecular risk prediction model that accurately identifies patients at high risk for EAC. Here, we investigated the impact of shortened telomeres in a mouse model for Barrett esophagus (L2-IL1B). The L2-IL1B mouse model is characterized by IL-1β-mediated inflammation, which leads to a Barrett-like metaplasia in the transition zone between the squamous forestomach and glandular cardia/stomach. Telomere shortening was achieved by mTERC knockout. In the second generation (G2) of mTERC knockout L2-IL1B.mTERC −/− G2 mice exhibited telomere dysfunction with significantly shorter telomeres as measured by qFISH compared to L2-IL1B mice, correlating with stronger DNA damage in the form of phosphorylation of H2AX (γH2AX). Macroscopically, tumor area along the squamocolumnar junction (SCJ) was increased in L2-IL1B.mTERC −/− G2 mice, along with increased histopathological dysplasia. In vitro studies indicated increased organoid formation capacity in BE tissue from L2-IL1B.mTERC −/− G2 mice. In addition, pilot studies of human BE-, dysplasia- and EAC tissue samples confirmed that BE epithelial cells with or without dysplasia (LGD) had shorter telomeres compared to gastric cardia tissue. Of note, differentiated goblet cells retained longer telomeres than columnar lined BE epithelium. In conclusion, our studies suggest that shortened telomeres are functionally important for tumor development in a mouse model of BE and are associated with proliferating columnar epithelium in human BE. We propose that shortened telomeres should be evaluated further as a possible biomarker of cancer risk in BE patients.

Analysis and pharmacological modulation of senescence in human epithelial stem cells

“…The analysis of the karyotypes of EEC-OMESCs treated with DAPT did not reveal any numerical or structural chromosomal abnormalities. However, both the telomere length and the number of passages in culture were increased, thus confirming that the elongation of telomeres is associated with an increased half-life of the cells (27). Our preliminary findings would therefore indicate that the use of DAPT could slow down the senescence of epithelial SCs from patients with EEC syndrome, thus suggesting interesting pharmacological opportunities for the treatment of these patients.…”

“…Telomeric signals within each ROI were then measured with the ImageJ program and the data of fluorescence intensity and area for each telomeric signal were obtained. RTL of each cell was calculated by multiplying the fluorescence intensity value of each telomeric signal with their corresponding areas and shown as arbitrary units 27 . Single values of RTL for each cell were obtained and the comparison of 10–20 RTL values was performed using Statgraphics Centurion (version 16.2) statistical program.…”

A Review of the Repair of DNA Double Strand Breaks in the Development of Oral Cancer

“…In non-proliferating cells, quiescent cells, or terminally differentiated cells, a DDR can be activated independently of telomere length. Telomere dysfunction combined with the activation of the DDR is thought to be a critical early event in the development of human cancer [103], a proposal that is supported by data from pre-cancer models [104], including OPMD [105,106].…”

Promises and Limitations of Current Models for Understanding Barrett’s Esophagus and Esophageal Adenocarcinoma

“… 19 In another study, knocking out telomerase RNA component ( Terc ) in the IL-1β mouse resulted in shorter telomeres and a trend toward increased dysplasia. 20 Yet another study overexpressed the Notch2 receptor in LGR5+ progenitor cells and found increased NF-kB and accelerated dysplasia. 21 When Notch2 was overexpressed in DCLK-1+ tuft cells, increased crypt fission was noted, suggesting a possible mechanism in the pathogenesis of GEJ tumors from gastric tuft cells.…”