Premature aging/senescence in cancer cells facing therapy: good or bad?

Abstract

Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent "proliferative arrest" commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions that must be addressed to fully understand the beneficial and detrimental impacts of cellular senescence during cancer therapy.

Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

“…Among these, most prominent are the SA proliferation arrest (SAPA), SA apoptosis resistance (SAAR) and the micro-environmentally active SA secretory phenotype (SASP) (Coppe et al, 2008;Goldstein et al, 2005;Hayflick and Moorhead, 1961;Hernandez-Segura et al, 2018;Malaquin et al, 2016;. The SAPA functions as a direct tumor suppressive mechanism and is largely mediated by two key tumor suppressor pathways: p53/p21 WAF1 and p16INK4A/Rb (Beausejour et al, 2003;Campisi and d'Adda di Fagagna, 2007;Narita et al, 2003;Rodier et al, 2007), although many other pathways contribute a large degree of redundancy in this program (Gonzalez et al, 2016;Hernandez-Segura et al, 2018;Munoz-Espin and Serrano, 2014). It is thought that the stability of the SAPA is maintained to a great extent through SA chromatin remodeling, in particular through the formation of SA heterochromatin foci (SAHF) at the loci of proliferation-promoting genes Zhang et al, 2007).…”

“…Alternatively, the growth factors, cytokines, chemokines, extracellular proteases, and extracellular matrix proteins that compose the SASP mediate senescent cells functions in tissue repair (Coppe et al, 2008; 4/36 Freund et al, 2010;Freund et al, 2011;Hoenicke and Zender, 2012;Krizhanovsky et al, 2008;Malaquin et al, 2016;Rodier et al, 2009). In the context of cancer, senescence is undoubtedly beneficial in its role as a barrier to malignant transformation in pre-neoplastic lesions (Campisi and d'Adda di Fagagna, 2007;Kuilman et al, 2010;Rodier et al, 2007), and therapy-induced senescence (TIS) in damaged cancer cells may also be advantageous by preventing tumor cell growth (Chang et al, 1999;Collado and Serrano, 2010;Gonzalez et al, 2016). However, alterations to tissue microenvironments caused by SASP must be evaluated contextually (Coppe et al, 2010).…”

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

“…The dose and time-dependence of radiation exposure can significantly alter the impact of RT on tumor microenvironment by affecting tumor or stromal cell behavior, migration, and treatment response (26,28,29,(83)(84)(85)(86)(87)(88)(89)(90). High-dose irradiation effects include hemorrhage, cognitive decline, neurodegeneration, and premature senescence, which can progress over time (91,92). To identify whether the 20Gy single dose led to aging-like metabolic phenotype or severe neurotoxicity, two aged-mice groups were included (aged (24mo) and aged-obese (24mo)) and their metabolic profiles were compared with 20Gy-IR in C57BL/6 mice cohorts.…”

Ribosomal stress-induced senescence as a novel pro-senescence strategy for p16 positive basal-like breast cancer

“…The application of specific chemotherapeutics frequently activates a cancer-cell senescence programme (termed therapy-induced senescence, TIS) in a wide array of tumours, including breast cancer 3 . Several studies show that cancer cell senescence can be activated via p53 restoration, telomerase inhibition or CDK modulation 3 , supporting targeted pro-senescence anti-cancer strategies 4 . The concept of activating this cellular programme for therapeutic gain in the most clinically challenging cancer subtypes is gaining momentum for two main reasons.…”