When Three Isn’t a Crowd: A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers

Genes

MarkS. Cragg¹  Talivaldis Freivalds²  Michael Hausmann³  Pawel Zayakin⁴  NinelM. Vainshelbaum⁴  Kristine Salmina⁴  Jekaterina Erenpreisa⁴  BogdanI. Gerashchenko⁵  Juris Erenpreiss⁶ 

[1] Centre for Cancer Immunology, University of Southampton, Southampton SO16 6YD, UK;Institute of Cardiology and Regenerative Medicine, University of Latvia, LV-1004 Riga, Latvia;Kirchhoff Institute for Physics, Heidelberg University, D-69120 Heidelberg, Germany;Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia;R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, 03022 Kyiv, Ukraine;Riga Stradins University, LV-1007 Riga, Latvia;

关键词: near-triploid cancer;    radioresistance;    chemoresistance;    reprogramming;    digyny;    polynuclear cancer cells;    tripolar mitosis;    pedogamy;    tumor blastomeres;   

DOI  :  10.3390/genes10070551

来源: DOAJ

【 摘 要 】

Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a conceptual framework of the digyny-like origin of this karyotype based on the germline features of malignant tumors and adaptive capacity of digyny, which supports survival in adverse conditions. Studying how the recombinatorial reproduction via diploidy can be executed in primary cancer samples and HeLa cells after DNA damage, we report the first evidence that diploid and triploid cell sub-populations constitutively coexist and inter-change genomes via endoreduplicated polyploid cells generated through genotoxic challenge. We show that irradiated triploid HeLa cells can enter tripolar mitosis producing three diploid sub-subnuclei by segregation and pairwise fusions of whole genomes. Considering the upregulation of meiotic genes in tumors, we propose that the reconstructed diploid sub-cells can initiate pseudo-meiosis producing two “gametes” (diploid “maternal” and haploid “paternal”) followed by digynic-like reconstitution of a triploid stemline that returns to mitotic cycling. This process ensures tumor survival and growth by (1) DNA repair and genetic variation, (2) protection against recessive lethal mutations using the third genome.

【 授权许可】

Unknown