Three steps to the immortality of cancer cells: senescence, polyploidy and self-renewal

Abstract

Metastatic cancer is rarely cured by current DNA damaging treatments, apparently due to the development of resistance. However, recent data indicates that tumour cells can elicit the opposing processes of senescence and stemness in response to these treatments, the biological significance and molecular regulation of which is currently poorly understood. Although cellular senescence is typically considered a terminal cell fate, it was recently shown to be reversible in a small population of polyploid cancer cells induced after DNA damage. Overcoming genotoxic insults is associated with reversible polyploidy, which itself is associated with the induction of a stemness phenotype, thereby providing a framework linking these separate phenomena. In keeping with this suggestion, senescence and autophagy are clearly intimately involved in the emergence of self-renewal potential in the surviving cells that result from de-polyploidisation. Moreover, subsequent analysis indicates that senescence may paradoxically be actually required to rejuvenate cancer cells after genotoxic treatments. We propose that genotoxic resistance is thereby afforded through a programmed life-cycle-like process which intimately unites senescence, polyploidy and stemness.

Atypical Cell Populations Associated with Acquired Resistance to Cytostatics and Cancer Stem Cell Features: The Role of Mitochondria in Nuclear Encapsulation

“…Neosis is considered as occurring in multinucleated postsenescent cells and as being characterized by karyokinesis via nuclear budding and asymmetric cytokinesis, producing aneuploid mononuclear cells with extended lifespans and transient stem cell features. It is believed that polyploid mother cells die after these events (Rajaraman et al, 2006;Erenpreisa and Cragg, 2013). Consequently, genotoxic resistance seems to be closely associated with reversible senescence, polyploidization, and stemness.…”

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…Indeed, it is reasonable to suggest that the unique mechanism of acquired resistance to metformin has opposing roles in growth and metastatic dissemination, while refractoriness to metformin limits breast cancer cell growth, likely due to an aberrant mitotic/cytokinetic machinery and accelerated autophagy, it notably increases the potential of metastatic dissemination by amplifying the number of pro-migratory and stemness inputs via the activation of a significant number of proteases and EMT regulators. Future studies should unambiguously elucidate whether our findings using supra-physiological concentrations of metformin mechanistically recapitulate the processes through which the induction of a migratory-stemness cellular state paradoxically occurs in a polyploid, senescent-autophagic scenario [102][103][104][105] that is triggered by the chronic metabolic stresses that commonly occur during cancer development and after treatment with cancer drugs.…”

Genome management and mismanagement—cell-level opportunities and challenges of whole-genome duplication

“…This is no surprise given the range of evolutionary trajectories that characterize diverse cancer types and the difficulty of obtaining a truly representative picture of the evolutionary paths that cell lineages follow within a single tumor (Gerlinger et al 2014b;Walther et al 2015). Beyond the unresolved population genetic considerations of the effects of variation in a polyploid context (e.g., see Otto and Whitton 2000;Gerstein and Otto 2009), on the phenotypic side, recent work suggested that polyploidy may indeed promote rampant aneuploidy and genetic and phenotypic diversity (Lagadec et al 2012;Erenpreisa and Cragg 2013;Zhang et al 2013). Furthermore, polyploid giant cells, which are often found in human solid tumors, are highly resistant to low oxygen conditions, cycle slowly (Zhang et al 2013), and have been proposed to also contribute to lineage expansion and heterogeneity upon induction by chemotherapy or radiation treatment (Lagadec et al 2012;Zhang et al 2013).…”