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-replication-cites, 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.
Highlights
The advantages/odds of eradicating cancer are the highest for knowledge of how cancer can arise: i.e., cellular mechanism(s) that can give rise to number one hallmark of cancer: fitness increased genome-changed cells [1]
S-chromosomal instability (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 slippage chromosome instability (S-CIN) mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process
Summary
The advantages/odds of eradicating cancer are the highest for knowledge of how cancer can arise: i.e., cellular mechanism(s) that can give rise to number one hallmark of cancer: fitness increased genome-changed cells [1]. The cancerous process, mostly un-curable, were proposed to happen by multiple, accumulating mutations (MT) [8] [9] in a normal body cell, despite the fact that the mutation rate for such cells is exceedingly low To accommodate this fact, a changed MT-theory proposed initiation by a mechanism of chromosomal instability (CIN) with the special feature of being inherited [10]. The origin of this thesis is based on a series of in vitro experiments from observations associated with natural telomere “breakage” and carcinogen-free, induced chromosomal breakage with a visual response of induced tetra- and endo-polyploid cells [18]-[27] These polyploid cells mechanistically, underwent genome reductive divisions, culminating in fitness increase (KW) of near-diploid human cells, as mentioned, a first required hallmark for tumorigenesis [1]. The purpose of this review is to bring into tumorigenesis, cellular consequences of reversible polyploidization (KW) in the context of current “cancer” thinking-and-doings in the search for novel, cancer therapy targets
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