The Dynamic Process and Its Dual Effects on Tumors of Therapy-Induced Senescence

Abstract

Cellular senescence is traditionally considered as stable cell cycle arrest state with other phenotypic alterations including the production of an array of cytokines and growth factors. Cancer cells undergo senescence in response to chemotherapeutic agents, radiotherapy and molecular targeted therapy. This form of senescence is termed therapy-induced senescence (TIS) and represents a desirable target in cancer therapy. Recent studies have shown that cellular senescence is a highly heterogeneous and dynamic process. Apart from being cleared by the immune system, the senescent cancer cells may survive for a long time and escape from senescence state. Notably, these cells even have the potential to regain stemlike state with high aggressiveness that eventually facilitates cancer recurrence. Furthermore, the senescence-associated secretory phenotype (SASP) of senescent cells is not always the same, and could establish immunosuppression and a protumor microenvironment. Given these detrimental effects, senescence-inducing chemotherapy followed by senotherapy (the "one-two punch" approach), has emerged. This combined therapy could mitigate unnecessary side effects of the persistent senescent cells, reduce the toxicity of pro-senescence therapy and prolong the survival of cancer patients, and it has a potential future in the precise treatment of cancer. Herein, we review the complex effects of therapy-induced senescence in cancer and highlight the great promise of two-step strategies in anticancer therapies.

Apoptosis as Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer

“…It is well described that cells unable to swiftly and fully repair DNA damage enter a "premature senescent" status, implying a stable inhibition of proliferation [34]. However, cancer cells can escape from senescence through epigenetic reprogramming [35], gaining malignancy [36,37]; this constitutes a concern, and senolytic treatments have been proposed as a way to limit therapy-induced senescence [38]. Escape from senescence relates especially with those cancer cells lacking key tumor suppressor gene expression, such as TP53 [39].…”

Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB‐mediated SASP in ionizing radiation‐induced senescence

“…This form of senescence can be induced by diverse stimuli. 29 For example, the exposure to DNA damaging agents such as ionizing radiation and various anti-cancer chemotherapy agents are known to give rise to a senescent phenotype in both normal and cancer cells, which is often termed 'Therapy-Induced Senescence' (TIS). 30 Inducing cancer cell senescence by chemotherapy and radiotherapy may provide an appealing option to limit cancer progression and to improve the prognosis of various solid and haematological malignancies.…”

“…Here, we developed a model of irradiation‐induced premature senescence, the so‐called SIPS. This form of senescence can be induced by diverse stimuli 29 . For example, the exposure to DNA damaging agents such as ionizing radiation and various anti‐cancer chemotherapy agents are known to give rise to a senescent phenotype in both normal and cancer cells, which is often termed ‘Therapy‐Induced Senescence’ (TIS) 30 .…”

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

“…Others and we have demonstrated that a complex mix of cytokines and growth factors sustains the emergence of cancer stem cell-like cell subpopulations in chemotherapy-treated cell lines and primary cultures, according to a Senescence-Associated-Secretory-phenotype (SASP) model [11,13,15]. However, onset of SASP takes days to weeks to occur [13,14,66,67] therefore we searched for earlier mediators of such a process. We tested here the hypothesis that metabolic remodeling in pemetrexed (pem) -treated cells could initiate the SASP-driven secretome rearrangement.…”