Abstract
The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model showed two succeeding phases: molecular mutations for initiation of fitness-gained cells, and large chromosomal changes to aneuploidy from inherited DNA-breakage-repair inaccuracies. The mutations were gained while DNA-repair and DNA-replication, co-existed in the route to tetraploidy, a phenomenon also expressed for some existing unicellular organisms. These organisms also showed genome reductive, amitotic, meioticlike division, and was the origin of human genome conserved, self-inflicted 90° reorientation of the 4n nucleus relative to the cytoskeleton axis. In the in vitro DNA-damage model, this remarkable 4n-event deciding “flat-upright” cell-growth characteristics showed several consequences, for example, cancer-important, E-cadherin-β-catenin cell-to-cell adherence destruction, which gave diploid progeny cells, mobility freedom from cell contact inhibition, likely in renewal tissues. This 4n-skewed division-system with inheritance in progeny cells for repeat occurrences as mentioned for flat-up-right growth patterns is similar to claimed concepts of metaplasia-EMT/MET embryogenesis events in cancer evolution. A scrutiny of this literature, proof-wise invalidated this embryological concept by tetraploid 8C cells occurring in MET events and, was noted for small cell occurrence, i.e., diploidy from 4n-8C reductive division, an also event for tumor relapse cells, derived from genome damaging therapy agents. Pre-cancer hyperplasia reported MSP, cadherincatenin destruction and 90° perpendicularity to basal cell membrane. The DNA-damage-repair model can weed-out therapy-agents triggering 4n-skewed division. Cancer-control, beginning-information, is likely from mutational identity of the 4n derived fitness-gained cells.
Highlights
Have we made cancer disease into a mysterious, complex issue much more than it really is, if so, why? The “big picture”, if staying within scientific reasons, is that too much faith has been placed on cancer cell, molecular sequencing for mutational know-ledge, being the definitive answer to a solution of the cancer-riddle [1] [2]
Experiments with induced endoreplication to 4n cells, did not show the desired result, but instead the 4n cells became division-arrested, being referred to as the tetraploid paradox [16] [17] [18]. Contrary to these results we found that another type of tetraploidy from DNA-repair induced mitotic slippage process (MSP) with re-replication of diploid cells, giving rise to tetraploid cells, but with 4-chromatid chromosomes, divided without any arrest-disturbances
The hyperplasia in vivo culminated in pathological dysplasia and the carcinoma phenotype, which is a first-time achieved “chain of events” from initiation to full-blown cancer
Summary
Have we made cancer disease into a mysterious, complex issue much more than it really is, if so, why? The “big picture”, if staying within scientific reasons (aside from commercial interest), is that too much faith has been placed on cancer cell, molecular sequencing for mutational know-ledge, being the definitive answer to a solution of the cancer-riddle [1] [2]. 30+ years later, there is an immense quantity of difficult to interpret mutational data, showing various types of molecular nucleotide lesions [1] [3] This overall “unsolvable” data has even led to the suggestion of needed mathematics for the understanding of tumorigenesis [4], which is occurring [5] [6] [7]. If a further weeding excludes carcinogen/viral experiments, which are not happenings for sporadic cancers, and a further elimination is done for ideas of initiation, deducted from cancer cell line-experiments, there are only a few qualifying sources left This latter dismissal (not effecting “progression” literature) is necessary, because such cancer cells are already positive for activated telomerase gene, associated with immortality, which normal human cells must gain. Somewhat debated is the suggestion of chromosomal instability (CIN) and/or a mutator mechanism in this multiyear evolution to malignancy [15]
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