Escape from senescence: molecular basis and therapeutic ramifications

Abstract

Cellular senescence constitutes a stress response mechanism in reaction to a plethora of stimuli. Senescent cells exhibit cell‐cycle arrest and altered function. While cell‐cycle withdrawal has been perceived as permanent, recent evidence in cancer research introduced the so‐called escape‐from‐senescence concept. In particular, under certain conditions, senescent cells may resume proliferation, acquiring highly aggressive features. As such, they have been associated with tumour relapse, rendering senescence less effective in inhibiting cancer progression. Thus, conventional cancer treatments, incapable of eliminating senescence, may benefit if revisited to include senolytic agents. To this end, it is anticipated that the assessment of the senescence burden in everyday clinical material by pathologists will play a crucial role in the near future, laying the foundation for more personalised approaches. Here, we provide an overview of the investigations that introduced the escape‐from‐senescence phenomenon, the identified mechanisms, as well as the major implications for pathology and therapy. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

“…Senescence induction is a mode of breast cancer survival that is garnering increased attention due to studies suggesting that reversible senescence may function as a mechanism of tumor dormancy ( 88 , 116 – 119 ). Although the relationship between senescence and antiestrogen resistance is not adequately defined, senescence is known to support dormant tumor cell survival ( 120 ), contribute to apoptosis resistance ( 121 ), cellular stemness, tumor aggressiveness ( 122 ), and the metastatic niche ( 123 ).…”

“…Importantly, autophagy and/or senescence induction have been identified as a pro-survival response to most antiestrogen treatments and molecular targeting currently being used for the treatment of ER + breast cancer. Although senescence was originally identified as a terminal state of cancer cells, recent studies have highlighted that senescence can be reversible, and thus, is a potential mechanism breast cancer cells can utilize to escape antiestrogeninduced and chemotherapy-induced stress (87)(88)(89). Thus, these "survival" response pathways often precede the genetic and epigenetic alterations required to escape cytostasis (likely contributing to tumor dormancy) and activate a functional cell cycle, with subsequent breast cancer cell proliferation.…”

Current Insights into Tissue Injury of Giant Cell Arteritis: From Acute Inflammatory Responses towards Inappropriate Tissue Remodeling

“…The SASP secretome includes a variety of proinflammatory mediators, chemokines, growth factors, angiogenic factors, bioactive lipids, and MMPs that may act in a paracrine or autocrine manner to induce senescence in vivo, triggering a positive-feedback loop that leads to the perpetuation of the inflammatory response [ 197 ]. Senescent cells have been identified in the context of human diseases, including COVID-19 [ 198 ], where senescent cells were detected in SARS-CoV-2-infected lung tissue, and Hodgkin lymphoma, where a high percentage of senescent cells were detected in the affected lymph nodes [ 199 , 200 ]. Our group has reported the presence of senescent cells in biopsy-proven GCA specimens [ 188 ].…”

Recent Advances in Pathology: the 2023 Annual Review Issue of The Journal of Pathology

“…The authors discuss in detail the individual secondary alterations described in mesenchymal tumours and how they promote sarcomagenesis mechanistically, organised by the hallmarks of cancer processes. The third review article on cancer mechanisms comes from Gorgoulis and colleagues in Athens, Greece, and in Manchester, Dundee, and Surrey, UK [11]. The authors discuss the recent advances in understanding how cellular senescence acts as a barrier to carcinogenesis, how senescence is induced by a variety of carcinogenic pathways, and the mechanisms by which cells can escape from senescence, a process that is distinct from senescence bypass.…”