Cancer Stemness: Senescence Escape
As mentioned above, cells undergoing senescence can still escape the senescence program and become malignant while acquiring additional mutations (519, 535, 536) (Figure 2). In our studies, we observed a spontaneous mutation [a deficiency in p19 (Arf)] in Ras-expressing hepatocytes, which resulted in a full-blown HCC development using a Ras-induced precancerous liver disease model (535, 536). The reversibility of TIS can be caused through the inactivation of tumor suppressors p53, p16 (Ink4A), p19 (Ink4d), and/or RB (504, 507, 519). Additionally, the over-expression of CDC2/CDK1 and survivin can promote cancer stem cell survival and can also promote the development of polyploidy (507). In general, mutations in CDKN2A, coding for p16 (Ink4a, CDKN2A), p21 (Waf1, CDKN1A), and p27 (Kip1, CDKN1B) as well as E2F3 and EZH2, and a high c-MYC expression might result in low percentages of senescent cells (504, 519). Moreover, particular mutations completely protect melanoma cells from cell cycle arrest upon chemotherapy: DMBC29 melanoma cells that carried a EZH2S412C mutation, expressed c-MYC at a low level and a wild type of CDKN2A did not undergo senescence, in contrast to many melanoma cells treated with vemurafenib and trametinib (519).
An escape of cells from senescence was also identified by Milanovic et al. in B-cell lymphoma studies (14). In those studies, the researchers showed that senescent cells substantially upregulated an adult tissue stem cell signature and activated Wnt signaling (14). This senescence-associated stemness was an unexpected cell-autonomous phenotype that caused the generation of cells with a higher tumorigenic potential in vitro (14).
However, escape from senescence is not the only pathway that promotes an increase in the cancer stemness phenotype. Stemness within the tumor tissue is also regulated indirectly by signaling molecules which support the maintenance of stemness in CSCs as well as non-CSCs, as described in the following sections.