'Neosis' describes the process whereby p53 function-deficient tumour cells undergo self-renewal after genotoxic damage apparently via senescing ETCs (endopolyploid tumour cells). We previously reported that autophagic digestion and extrusion of DNA occurs in ETC and subsequently revealed that self-renewal transcription factors are also activated under these conditions. Here, we further studied this phenomenon in a range of cell lines after genotoxic damage induced by gamma irradiation, ETO (etoposide) or PXT (paclitaxel) treatment. These experiments revealed that chromatin degradation by autophagy was compatible with continuing mitotic activity in ETC. While the actively polyploidizing primary ETC produced early after genotoxic insult activated self-renewal factors throughout the polygenome, the secondary ETC restored after failed multipolar mitosis underwent subnuclei differentiation. As such, only a subset of subnuclei continued to express OCT4 and NANOG, while those lacking these factors stopped DNA replication and underwent degradation and elimination through autophagy. The surviving subnuclei sequestered nascent cytoplasm to form subcells, while being retained within the confines of the old ETC. Finally, the preformed paradiploid subcells became released from their linking chromosome bridges through autophagy and subsequently began cell divisions. These data show that 'neotic' ETC resulting from genotoxically damaged p53 function-deficient tumour cells develop through a heteronuclear system differentiating the polyploid genome into rejuvenated 'viable' subcells (which provide mitotically propagating paradiploid descendents) and subnuclei, which become degraded and eliminated by autophagy. The whole process reduces aneuploidy in descendants of ETC.

Recent findings including computerised live imaging suggest that polyploidy cells transiently emerging after severe genotoxic stress (and named 'endopolyploid cells') may have a role in tumour regrowth after anti-cancer treatment. Until now, mostly the factors enabling metaphase were studied in them. Here we investigate the mitotic activities and the role of Aurora-B, in view of potential depolyploidisation of these cells, because Aurora-B kinase is responsible for coordination and completion of mitosis. We observed that endopolyploid giant cells are formed via different means in irradiated p53 tumours, by: (1) division/fusion of daughter cells creating early multi-nucleated cells; (2) asynchronous division/fusion of sub-nuclei of these multi-nucleated cells; (3) a series of polyploidising mitoses reverting replicative interphase from aborted metaphase and forming giant cells with a single nucleus; (4) micronucleation of arrested metaphases enclosing genome fragments; or (5) incomplete division in the multi-polar mitoses forming late multi-nucleated giant cells. We also observed that these activities can release para-diploid cells, although infrequently. While apoptosis typically occurs after a substantial delay in these cells, we also found that approximately 2% of the endopolyploid cells evade apoptosis and senescence arrest and continue some form of mitotic activity. We describe here that catalytically active Aurora-B kinase is expressed in the nuclei of many endopolyploid cells in interphase, as well as being present at the centromeres, mitotic spindle and cleavage furrow during their attempted mitotes. The totally micronucleated giant cells (containing sub-genomic fragments in multiple micronuclei) represented only the minor fraction which failed to undergo mitosis, and Aurora-B was absent from it. These observations suggest that most endopolyploid tumour cells are not reproductively inert and that Aurora-B may contribute to the establishment of resistant tumours post-irradiation.

This paper summarizes the works published by author and his co-workers in the Russian journal Tsitologiya concerning endopolyploidy in mollusks and appraises this phenomenon in general. Both ontogenetic and phylogenetic aspects of endopolyploidy have been studied. In the snail Succinea lauta, a complex examination of endomitosis has been performed. A regular replacement of the normal (complete) proliferative mitosis by abnormal (incomplete) restitutional mitosis, and then by Geitler's classic endomitosis has been demonstrated. We examined 29 bivalve and 82 gastropod species for the presence of polyploid cells in glandular tissues and ganglia. In the bivalve species, ordinary diploid cells form various tissues, while in the gastropods, the role of polyploidy in tissue development appears to increase in phylogenesis. The rise of endopolyploidy and cell giantism in histogeneses of a variety of animal and plant species is widely known. It is believed to be a regular event in the evolution of certain groups. To give a universal interpretation of endopolyploidy, we proposed that a single polyploid cell be better considered as an endoclone. In this case, evolutionary transformation of diploid cell clones into polyploid endoclones may be viewed as Dogel's oligomerization applied to cell-tissue level. From this viewpoint, major properties of an oligomerized system (intensification of function, functional efficiency (ergonomy), increased genomes reliability, simplification of the intra- and supersystem regulations, and acceleration of development) can be considered as principal peculiarities of polyploid growth strategy. The above peculiarities allow one to consider endopolyploidy as an additional means of integrative onto(histo)genetic regulations and correlations and as an important evolutionary factor (coordinations) acting through natural selection. Thus, in general, endopolyploidy is an adaptive morphogenetic factor, but its concrete role may differ in different tissues and organisms depending on cell specialization and histogenetic particularities.

No abstract

No abstract