**1. Introduction**

In 2001 Roninson and colleagues [1] published the now seminal article entitled "If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells". After decades

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of overwhelming attention toward apoptosis induction as the cure for cancer, this article gave birth to a new field in cancer research. They wrote: "Inhibition of the program of apoptosis has been reported to have little or no effect on clonogenic survival after treatment with drugs or radiation in several tumor cell lines. A decrease in apoptosis is compensated in such cell lines by an increase in the fractions of cells that undergo permanent growth arrest with phenotypic features of cell senescence. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may produce secreted proteins with potential tumor-promoting activities."

Since that article, the induction of senescence was even claimed as the new goal of cancer treatment [2] and many researchers stepped on this path.

In this chapter, we describe our data over the last 2 decades, which along with other research, substantiates the exact opposite: that so-called accelerated cell senescence (ASC) (also called stress-induced premature senescence) and mitotic catastrophe (MC) are not desired goals of cancer treatment. Rather, we show that these processes can enable genotoxically treated cancer cells to escape cell death, not only by secretion of survival promoting components [3] but also by effective DNA repair. By stabilizing or recovering the innate stem properties of cancer stem cells (CSCs) senescence can be reversed by DNA damaged-induced ACS. To explore these concepts clearly it is first important to review and define the typical features of cell senescence and the biology of CSCs.

### **2. Biological features of cell senescence: what is clear and what is not?**

Replicative senescence is usually dependent on *TP53*/p21CIP1/pRb/E2F pathway, whereas accelerated senescence can be mediated through *TP53*/p21CIP1/pRb/E2F or, p16ink4a/pRb/ E2F pathway or both [4]. Cells acquire flat morphology, upregulate autophagy, and become positive for sa-β-galactosidase (pH 6.0) staining, indicative of high lysosomal activity. Erosion of telomeres and achievement of the Hayflick limit characterizes proliferative senescence, while in ACS the telomeres are not shortened [5]. However, the emergence of DNA strand breaks and the resulting DNA damage response (DDR) characterizes both proliferative and accelerated senescence [6]. Persistent irreparable DNA damage triggers the senescence-associated secretome [7], which is another feature of cell senescence. Emergence of endopolyploid cells, some capable of escaping senescence is also a typical feature of normal [8] and cancer cells [9, 10]. The reversibility of genotoxically induced senescence coupled to reversible polyploidy and its relation to stemness and population recovery are key phenomenon to understand if we wish to develop better cancer treatments [11–17]. The polyploidy component of senescence is associated with resistance to chemotherapy and involves mTOR activation; its inhibition causes senescence reversal, neo-expression of stem cell markers [18] and increased resistance of cancer cells to chemotherapy [19]. However, whether any senescing primary somatic cancer cell is capable of displaying the above features associated with senescence reversal or whether this only applies to cancer stem cells (CSCs) and how the recovery finally occurs is still largely unclear.
