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Genes (Basel). 2019 Jan 25;10(2). pii: E83. doi: 10.3390/genes10020083.

The Cancer Aneuploidy Paradox: In the Light of Evolution.

Author information

1
Latvian Biomedical Research and Study Centre, LV1067 Riga, Latvia. salmina.kristine@gmail.com.
2
Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France. anda.huna@gmail.com.
3
Riga Stradins University, LV1007 Riga, Latvia. m.kalejs@gmail.com.
4
Latvian Biomedical Research and Study Centre, LV1067 Riga, Latvia. dace@biomed.lu.lv.
5
Bundeswehr Institute of Radiobiology affil. to the Univ. of Ulm, 80937 Munich, Germany. scherth@web.de.
6
Centre for Cancer Immunology, University of Southampton, Southampton SO16 6YD, UK. m.s.cragg@soton.ac.uk.
7
Latvian Biomedical Research and Study Centre, LV1067 Riga, Latvia. katrina@biomed.lu.lv.

Abstract

Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform the segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and a homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ-H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or by radial cytotomy including pedogamic exchanges) and by the release of secondary cells and/or the formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle checkpoint. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer.

KEYWORDS:

aneuploidy; autokaryogamy; cancer; chromothripsis; cleavage embryo; disabled spindle; meio-mitosis; recombination on kinetochores; reduction; somatic pairing

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