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

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.

VACCINATION of Atlantic salmon leads to long-lasting higher levels of serum immunoglobulin and possible skewed ratios of two distinct IgM isotypes

Primary and secondary antibody responses in blood of teleost fish are mainly IgM mediated, as they lack an IgG homolog and a class switch mechanism. Thus, the major serum immunoglobulin is tetrameric IgM. A unique antibody class in teleosts;named IgT, appears to be specialized for mucosal immunity and is present in low concentrations in serum. A third class;IgD was recently detected in serum of rainbow trout, but is less abundant than IgT. In the present study, relative quantification of total IgM showed that Atlantic salmon (Salmosalar) which had received an oil-adjuvanted commercial vaccine maintained about 2-fold higher levels of IgM;14 and 17 months after intraperitoneal injection, in comparison to unvaccinated fish kept in the same cage. Similar results were obtained by ELISA (serum IgM) and reverse transcription real time PCR (spleen mRNA). Analyses conducted in our lab have shown that several salmonid species possess two slightly different IgM isotypes as a result of ancestral tetraploidy. In Atlantic salmon, two distinct IgM subpopulations (A and B) can be separated by anion exchange chromatography. The IgM-B tetramer exhibits a higher degree of disulfide cross-linking than IgM-A, presumably due to an extra cysteine near the C-terminus of the heavy chain. The typical A/B ratio is approximately 40/60. Anion exchange elution profiles of serum IgM from vaccinated fish indicate that prolonged triggering of the immune system can lead to a skewed ratio of IgM-A/IgM-B. In the context of recent results from rainbow trout (Onchorhynchusmykiss), showing that high affinity antibodies are more highly polymerized and have a longer half life time, Atlantic salmon is an interesting model to elucidate these aspects further since tools are available to distinguish IgM-A and IgM- B in this species.

Epigenetic Enabled Normal Human Cells, Lead to <i>First Cell</i>’s Unique Division System, Driving Tumorigenesis Evolution

Normal cells must become cancer-enabling before anything else occurs, according to latest literature. The goal in this mini-review is to demonstrate special tetraploidy in the enabling process. This we have shown from genomic damage, DDR (DNA Damage Response) activity with skip of mitosis leading to diploid G2 cells at the G1 border in need of chromatin repair for continued cell cycling to the special tetraploid division system. In several studies specific methylation transferase genes were activated in normal human cells in tissue fields, containing different cell growth stages of the cancerous process. Histology studies, in addition to molecular chemistry for identification of oncogenic mutational change, were a welcome change (see below). In a study on melanoma origin, DDR also showed arrested diploid cells regaining cycling from methylation transferase activity with causation of 2n melanocytes transforming to 4n melanoblasts, giving rise to epigenetic tumorigenesis enabled First Cells. Such First Cells were from Barrett’s esophagus shown to have inherited the unique division system from 4n diplochromosomal cells, first described in mouse ascites cancer cells (below). We discovered that the large nucleus prior to chromosomal division turned 90° relative to the cytoskeleton axis, and divided genome reductive to diploid, First Cells, in a perpendicular orientation to the surrounding normal cells they had originated from. This unique division system was herein shown to occur at metastasis stage, implying activity throughout the cancerous evolution. Another study showed 4-chromatid tetraploidy in development to B-cell lymphoma, and that such cancer cells also proliferated with participation of this unusual division system. Such participation has long been known from Bloom’s inherited syndrome with repair chiasmas between the four chromatids, also an in vitro observation by us. Our cytogenetic approach also revealed that they believed mitotic division in cancer cells is wrong because such cell divisions were found to be from an adaptation between amitosis and mitosis, called amitotic-mitosis. Amitosis means division without centrosomes, which has long been known from oral cancer cells, in that MOTCs (microtubule organizing center) were lacking centrioles. This observation calls for re-introduction of karyotype and cell division studies in cancer cell proliferation. It has high probability of contributing novel approaches to cancer control from screening of drugs against the amitotic-mitotic division apparatus.