Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

Abstract

In contrast to the well-recognized replicative and stress-induced premature senescence of normal somatic cells, mechanisms and clinical implications of senescence of cancer cells are still elusive and uncertain from patient-oriented perspective. Moreover, recent years provided multiple pieces of evidence that cancer cells may undergo senescence not only in response to chemotherapy or ionizing radiation (the so-called therapy-induced senescence) but also spontaneously, without any external insults. Since the molecular nature of the latter process is poorly recognized, the significance of spontaneously senescent cancer cells for tumor progression, therapy effectiveness, and patient survival is purely speculative. In this review, we summarize the most up-to-date research regarding therapy-induced and spontaneous senescence of cancer cells, by delineating the most important discoveries regarding the occurrence of these phenomena in vivo and in vitro. This review provides data collected from studies on various cancer cell models, and the narration is presented from the broader perspective of the most critical findings regarding the senescence of normal somatic cells.

Keywords: Cancer biology; Cellular senescence; Spontaneous senescence; Therapy-induced senescence.

Fig. 1

A hypothetical, cancer-modulating loop formed by normal stromal cells interacting with cancer cells undergoing therapy-induced senescence. According to the current knowledge, the phenomenon of cellular senescence may apply to either normal or cancer cells forming a tumor. In contrast to well-established cancer-promoting activity of senescent stromal cells, the outcomes of senescent cancer cells may be both pro- and anti-tumoral. It is still unknown whether senescent cancer cells may contribute to the induction of senescence in normal cells, e.g., via the SASP. DDR DNA damage response, EMT epithelial–mesenchymal transition, NTE radiation-induced non-targeted bystander, SASP senescence-associated secretory phenotype

Fig. 2

Therapy-induced senescence of cancer cells from the perspective of the ambivalent, either positive or negative outcomes of this process for a patient

Fig. 3

Theoretical triggers of spontaneous senescence of cancer cells in the context of plausible biological activities of these cells. According to the literature, spontaneous senescence of cancer cells may be a complex phenomenon, elicited in vivo by various kinds of stressors of both exogenous and endogenous nature. Spontaneously senescent cancer cells display similar phenotype to normal senescent cells and cancer cells undergoing IR or chemotherapy, including the development of SASP and increased oxidative stress. The SASP may further lead to the exacerbation of cancer progression, but at the same time, its elements can also be responsible for spreading of senescence among nearby proliferating cells, simultaneously with pro-senescence effects generated by oxidative stress