Stress-induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression

Abstract

Cellular senescence has long been considered to act as a tumor suppressor or tumor suppression mechanism and described as a phenomenon of irreversible cell cycle arrest. Cellular senescence, however, is now considered to have physiological functions other than tumor suppression; it has been found to be involved in embryogenesis, tissue/organ aging, and wound healing. Surprisingly, cellular senescence is also demonstrated to have a tumor progressive role in certain situations. Senescent cells exhibit secretory phenotypes called senescence-associated secretory phenotype (SASP), which secrete a variety of SASP factors including inflammatory cytokines, chemokines, and growth factors, as well as matrix remodeling factors that promote the alteration of neighboring tissue microenvironments. Such SASP factors have been known to drive the mechanisms underlying the pleiotropic features of cellular senescence. In this review, we examine current knowledge of cellular senescence at molecular and cellular levels, with a focus on chronic inflammation and tumor progression. senescence, senescence-associated secretory phenotype (SASP), reactive oxygen species (ROS), ionizing radiation, heat shock response (HSR) Hayflick and Moorhead 1) were the first to describe the limited divisions of cells and term this irreversible cell cycle arrest as cellular senescence. Senescent cells remain metabolically active, but their growth is irreversibly halted and their morphological characteristics altered as large, flat, and refractile 2,3). Irreversible cell cycle arrest is now thought to be dependent upon the shortening of telomeres; an expression of the catalytic subunit of the telomerase holo-enzyme (hTERT) is enough to bypass cellular senescence 4-6). Telomeres are folded d-loop/t-loop structures located at the ends of chromosomes that serve to mask DNA ends from being recognized as DNA double-strand-breaks (DSBs) 7,8). Telomerase activity is absent from most normal human somatic cells. After serial divisions, telomeres become too short to have sufficient binding sites for shelterin proteins (the latter being protein complexes known to protect telomeres) and are remodeled with a "capped" structure 9). Telomere shortening-related senescence is called replicative senescence. Nonetheless, mouse Current knowledge of molecular and cellular biology of cellular senescence S. Kobashigawa et al.

Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

“…Cell cycle arrest in senescence is largely mediated via activation of either one or both p53/p21 WAF1/CIP1 and p16 INK4A /pRB tumor suppressor pathways ( Rovillain et al, 2011 ; Kobashigawa et al, 2019 ; Liu and Wan, 2019 ). Both these pathways are complex as they involve many upstream regulators and downstream effectors along with varying side branches ( Chau and Wang, 2003 ; Levine and Oren, 2009 ).…”

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

“…However, senescence may occur in terminally differentiated cells demonstrating that senescence is not dependent on an active cell cycle ( Jurk et al, 2012 ; von Zglinicki et al, 2021 ). The activation of the p53/p21 WAF1/CIP1 and p16 INK4A /RB tumor suppressor pathways controls the cell cycle exit ( Herranz and Gil, 2018 ; Kobashigawa et al, 2019 ; Liu and Wan, 2019 ) as discussed below.…”