The Role of Cellular Senescence in the Gastrointestinal Mucosa

Abstract

Cellular senescence is a biologically irreversible state of cell-growth arrest that occurs following either a replicative or an oncogenic stimulus. This phenomenon occurs as a response to the presence of premalignant cells and appears to be an important anticancer mechanism that keeps these transformed cells at bay. Many exogenous and endogenous triggers for senescence have been recognized to act via genomic or epigenomic pathways. The most common stimulus for senescence is progressive loss of telomeric DNA, which results in the loss of chromosomal stability and eventual unregulated growth and malignancy. Senescence is activated through an interaction between the p16 and p53 tumor-suppressor genes. Senescent cells can be identified in vitro because they express senescence-associated β-galactosidase, a marker of increased lysosomal activity. Cellular senescence plays an integral role in the prevention and development of both benign and malignant gastrointestinal diseases. The senescence cascade and the cell-cycle checkpoints that dictate the progression and maintenance of senescence are important in all types of gastrointestinal cancers, including pancreatic, liver, gastric, colon, and esophageal cancers. Understanding the pathogenic mechanisms involved in cellular senescence is important for the development of agents targeted toward the treatment of gastrointestinal tumors.

Advanced glycation end‐products accelerate the cardiac aging process through the receptor for advanced glycation end‐products/transforming growth factor‐β‐Smad signaling pathway in cardiac fibroblasts

“…AGE are reported to be related to the prognosis and severity of heart failure, and predict cardiovascular disease mortality in older adults, which contribute to the increased myocardial stiffening of aging through cross‐linking elastin and collagen, and the development of cardiac fibrosis, promoting accumulation of collagen, stimulating inflammation and oxidative stress mediated by its receptor, RAGE . In the present study, we found that the activity of SA‐β‐Gal, a useful biomarker for cell senescence, was upregulated by AGE in rat cardiac fibroblasts. Furthermore, increased expression of P16 protein was detected in AGE‐treated cardiac fibroblasts.…”

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

“…Both chronic inflammation and ongoing exposure to an acid and bile containing gastroesophageal refluxate are considered to be important pathogenic factors in the development of BE and EAC [3][4][5]. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation associated carcinogenesis [6][7][8][9][10].…”

“…In BE and upper gastrointestinal cancer, including EAC, altered lysosomal function and activity and expression of factors involved in the lysosomal pathway have been reported [6,7,9,10]. Lysosomes are intracellular organelles that are known to be involved in processing waste products and are important regulators in intracellular homeostasis [12].…”

Regional heterogeneity in rat Peyer’s patches through whole transcriptome analysis

“…In the gut, this pathway prevents the development of various gastrointestinal cancers. 14 In contrast, sirtuin signaling delays senescence and further prolongs cellular life expectancy. 15 Members of the sirtuin family have been connected to obesity and related comorbidities, and in recent literature, connected to inflammation.…”