Normal Human Cells Acquiring Proliferative Advantage to Hyperplasia-Like Growth-Morphology: Aberrant Progeny Cells Associated With Endopolyploid and Haploid Divisions

Abstract

<p>Today, cancer-patients can seek individual genomic tailored therapy, but at escalating costs. However, cancer-incidence reduction would reduce such health-cost. The essence of this report is a cell-culture experimental approach for the production of genetically unstable cells from normal cells which with accumulation of “mutations” might reveal early, neoplastic-like pathology. Summarily the experimental focus was on: 1) establishment of a simple nutritional method (amino acid deprivation) for young-cell-response with depoly-ploidization of endopolyploid cells to diploid CIN-cells, 2) a first time observation of a fast growing new, small cell-type, appearing time-correlated with haploid segregations in normal, fibroblast metaphases and 3) growth characteristics of the progeny cells in 1) and 2) which from their young-cell derivation, could be growth-extended in cultural passages. This would hypothetically model early tumorigenic progression from normal cells. These studies revealed gain of proliferative advantage (GPA), multilayered, changed patterns of growth, focal 3-D cell-heaps with cell polarity change, and star-like mitotic forms. Comparatively, these developments were typical of hyperplasias. The transiency of the originating genome reductive mechanisms may have prevented earlier detections. It is discussed that present growth-changes were responses to homozygous-caused loss of heterozygosity (LOH) of putative pro-proliferation genetics, whereas leukemic and some solid tumor cells showed hemizygous-caused LOH in near-haploid clonal proliferations. The practical outcome is an experimentally simple, nutrition-based model system for SNP-based haplo-karyotyping of the two aberrant cell-types with GPA, which is a cancer, fundamental trait. Never before have cellular mechanism been shown to initiate in normal, human cells, neoplastic-like proliferative responses.</p

Neoplastic-Like CELL Changes of Normal Fibroblast Cells Associated with Evolutionary Conserved Maternal and Paternal Genomic Autonomous Behavior (Gonomery)

“…Although the lymphocyte, leukemias are very rarer, the haploidization process to mat and pat genomes may itself have a higher rate, but hidden in aneuploid-UPD-type hyperdiploidy from genomic duplication [86] No-where in the literature on cancer-biology has gonomery-based functional divisions with cell volume reduction to 1/2-size compared to normal cells of origin, been considered to play roles in cancer initiation and/or progression. The 1/2-size reduction is in agreement with origin from single territories [13] [74]. Such segregations are not restricted to diploid cells, because preliminary observations indicate that it also occurs for endotetraploid cells (see above).…”

“…But in either case the first meiotic-like (ML-1) division has probability of abnormal aneuploid chromosomal distribution, the whole chromosomal loss-type [44] that however, can be hidden by compensated uniparental disomy (UPD) [45]. These potentially, unstable divisions may also be associated with breakage [13] [14] with possibility for chromosomal rearrangements that can lead to segmental UPDs [46]. Certainly, if diplo-chromosomal structure can be modified into units there would be provisions for genomic diversity leading to clonal selection of cells with GPA from loss of heterozygosity (LOH).…”

“…But when one-step-meiosis was acknowledged, the assumed mechanistic route from diploidy to haploidy was believed to be a series of mitoses with gradual chromosome loss from non-disjunction [16], -not unlike today's suggestion for certain leukemias (see below). However, the most recent study of diploid yeast cells showed: "---rapid conversion to haploid ---DNA content ---" [66], and likewise rapid, for human-cell-haploidization (Figure 3(C)-(H)) from a haploid grouping process (Figure 3(D), Figure 3(E)) of chromosomes in normal metaphase cells [13] [14]. Such rosette-figures segregated near-haploid (~23) genomes by a halving-process of the chromosomal rings, which proceeded with telophase nuclei performing cytokinesis, and further to mitosis from genomic doubling (assumed as for terratomas) to homozygous cells.…”

“…Special division-systems that can bypass active, mitotic checkpoint control (p53-positive cells) have (so far) not been considered in the origin of the so-called transformed cell-phenotype. Since this latter process has recently been shown to occur for young cells with long telomeres [13] [14] it is very important that pre-cancer-like cell changes are recognized with origin from an endo-polyploid mechanistic cell division-system.…”

“…For the present presentation this latter suggestion is crucial, because it brings into the ongoing debate (see above) endo-polyploidy from endomitosis (the megakaryocyte type). For in vitro cells endotetraploidy with 4-chromatid chromosomes (diplochromosomes/pairs of sister chromosomes), the "Hurst-Nurse-type" recombinant repair of genomic damage was evident from tritiated thymidine labeling, and from chiasma-terminalization in anaphase [13] [18]. Such mitotic, chiasmatic exchanges between sister-chromatids of diplochromosomes (4n/8C) is also part of the disease picture for the prototype "cancer-model" Blooms' syndrome [19].…”