Mitotic Slippage Process Concealed Cancer-Sought Chromosome Instability Mechanism (S-CIN)

Abstract

Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer initiation, and on the question of a mechanism for inherited CIN (chromosomal instability). Evidence for fitness increased cells from the mitotic slippage process (in vivo/in vitro) originated from genome damaged diploid cells in G2/M, skipping mitosis to G1, which illegitimately permitted S-phase re-replication of the chromatid cohesed-2n cells to 4n-tetraploidy. During which, down-load of genome-wide cohesin occurred, producing 4-chromatid diplochromosomes, evolutionary conserved in repair of DNA. This type of 4n cells divided 2-step meiotic-like, leading to diploid aneuploid cells with increased fitness, and expression of gross chromosomal anomalies in proliferation. The diploid cohesed chromatids during re-replication would hinder replication of sticky heterochromatic regions, resulting in their under-replication, and known from Drosophila. The human chromosomes are longitudinally differentiated into satellite DNA regions, folic acid sensitive sites and the primary constriction (centromere); they are breakage sensitive regions and being heterochromatic. This strongly suggests, multiple, chromosomal regional under-replicationcites, translated to origin of slippage, S-CIN, a genome inherited destabilization mechanism. Logically, S-CIN would affect genes differentially depending on chromosome location, for example, the high frequency in cancers of mutated p53 on the small 17p-arm, which with centromere breakage would be preferentially lost in mitosis. This likely S-CIN mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process.

Genomic Instability in Cancer I: DNA-Repair Triggering Primitive Hereditary 4n-Skewed, Amitotic Division-System, the Culprit in EMT/MET/Metaplasia Cancer-Concepts

“…Strangely, these 6 cellular occurrences appear to be similar to those claimed in tumorigenesis from embryological-like EMT/MET events [27] [66]. The goal in these ongoing, high-interest studies, centers on definitions of genes controlling EMT/MET in embryology, being biomarkers for therapy in tumorigenesis [21] [116]. For example, the EMT was described as phases with "rapid changes in cellular phenotypes", such as: "-epithelial cells down-modulate cell-cell adhesion structures, alter their polarity, reorganize their cytoskeleton, and become isolated, motile" [115].…”

“…In the DNA-damage-repair, MSP in vitro model, such 4n cells were products from first equational division of 4n/8C/M > 4n/4C/G1, followed by more rarer, reductive fission-division of the 4n/4C/G1 cells to the fitness gained diploid cells (see above). In hyperplasia (fitness gained cells) of BE, 4n/8C cells were found to segregate with reductive division to hyperplastic diploid cells [21] [81], and in colon crypt cells with mutated APC gene, MSP was implicated in the production of the 4n/4C/G1 accumulating cells [70]. But most importantly, the hyperplastic crypt cells showed, measured, 90˚ cell polarity axial change, relative to the basement membrane [70].…”

“…Secondly, this BE occurrence was preceded by acid reflux disease, which caused genomic damaged cell-lesions in normal epithelium. Another interesting observation, hinting 4n-skewed cell division from the lesion with chromosomal damage (acid caused), is that in BE hyperplasia pre-cancer lesions, 4n-cells, cytometry isolated, in cell culture, were shown to cycle with reductive division back to shape-changed proliferative diploid cells [21] [81]. Other such pre-cancers have shown activated, genome-damage repair foci (γH2AX) distributed over the genome with chromosome locations [112].…”

“…The agreement with Rubin, is in heritability of the 4n-skewed, amitotic, division-system (cycling in BE [81]) providing CIN and mutator mechanism for genetic/epigenetic variability in cancer evolution (in prep.) [19] [20] [21].…”

Genomic Instability in Cancer II: 4N-Skewed (90°) Reductive Division via Fragile Sites to Fitness Increase for Solid and Hematological Cancer Beginnings

“…Unknown in all of this information is however, the most important question: how these malignancies were initiated. Tentatively we propose that some cells with nuclear rift-caused genomic damage, and can repair while the cell continues replication [70] [90] with outcome of the 4n-skewed division system, and its multiple consequences [100] ( Table 1 & Table 2).…”