The Cancer Aneuploidy Paradox: In the Light of Evolution

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 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 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 with radial cytotomy including pedogamic exchanges) and release of secondary cells and/or formation of an embryoid.  Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle and meiotic SC checkpoints. 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.

The Chromatin Extrusion Phenomenon in Amoeba proteus Cell Cycle

“…,b; Salmina et al. ). One of the depolyploidization mechanism implemented by tumour cells is the elimination of “excessive” chromatin by its extrusion from the nucleus into the cytoplasm.…”

The ectopic expression of meiCT genes promotes meiomitosis and may facilitate carcinogenesis

“…DMC1 mediates interhomolog DNA strand invasion [124] and is required for meiotic crossovers [125]. Recent studies have demonstrated that the DMC1 protein is ectopically expressed in Sézary patient lymphocytes [8], CTCL biopsy samples [24], cervical, colon and breast cancer cell lines [126][127][128], as well as in glioblastoma [129]. In addition, DMC1 mRNA expression has been observed in Burkitt's lymphoma and human lymphoblastoid cell lines [130].…”

“…In addition, DMC1 mRNA expression has been observed in Burkitt's lymphoma and human lymphoblastoid cell lines [130]. Interestingly, the upregulation of the DMC1 protein and mRNA was shown in several cell lines in response to irradiation-induced DSB formation and damage repair [126][127][128][129][130]. Ionizing radiation (IR) produces reactive oxygen species in proliferating cancer cells that leads to the generation of DSBs and activation of HR or NHEJ repair pathways [129,131,132].…”

“…Research shows that REC8 is also expressed in normal somatic cells [18]. Notwithstanding, much of the literature still refers to REC8 as a meiotic gene and it is still recognized as a CT antigen [128]. However, since it can be expressed in somatic tissues, it may be difficult to define its role in meiomitosis.…”

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

“…It is nowadays viewed as a kind of parasexual somatic reduction division, which transforms senescence cells into neoplastic ones and therefore plays and important role, especially in the formation, maintenance and progression of particular types of epithelial tumors. Analogous to meiotic recombination events, the reactivation of a meiotic program in mitotic somatic cells, meiomitosis, generates DNA double strand breaks that instigate repair activities, which in turn fabricate a plethora of structural rearrangements (Kalejs et al, 2006;Grichnik, 2008;Ianzini et al, 2009;Lindsey et al, 2013;Walen, 2014;Tsang et al, 2018;Salmina et al, 2019b).…”