ABSTRACT
In a series of publications, the hypothesis of a special-type of
endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the
initiation of tumorigenesis has been presented from in vitro experiments. This review uses cellular happenings in
benign pre-neoplasia to substantiate this idea, which appears to be linked to
the wound-healing process of injured tissue. Rarer association between a wound
healing process and a cancer occurrence has long been known. The wound healing
multi-program-system involved a phase of tetraploidy that showed
diplochromosomes. The hypothesis is that the inflammatory phase may not always
be sufficient in getting rid of dead and damaged cells (by apoptosis and
autophagy), such that cells with genomic damage (DNA breakage) may survive by
genomic repair associated with change to diplochromosomal tetraploidy. In vitro data have shown division of
these cells to be an orderly, mechanistic two-step, meiotic-like system,
resulting in only two types of progeny cells: 4n/4C/G1 and 2n/2C/G1 pseudo-diploid
cells with hyperplastic-like growth-morphology. In vivo damage to tissues can be from many sources for example,
physical, toxic environment or from a disease as in Barrett’s esophagus (BE)
with acid reflux into the esophagus. For this condition, it is acknowledged
that damage of the esophagus lining is a pre-condition to hyperplastic lesions
of pre-neoplasia. These initial lesions were from “diploid” propagating cells
and, 4n cells with G2 genomic content (no mitosis) accumulated in these lesions
before a change to dysplasia. Cell cycle kinetics put these 4n cells in G1,
which with S-phase entry would lead to asymmetric tetraploid mitoses,
characteristic for dysplastic lesions. This change in hyperplasia to dysplasia
is the root-essential condition for a potential progression of pre-neoplasia to
cancer. In BE the hyperplastic lesion showed increasing gains of cells with
inactivated p53 and p16[ink4a] genes, which destroyed the retinoblastoma (Rb)
protein-control over S-phase entry from G1. Rb-protein is a key controller of
cycling advancement from G1 (also for normal cells), and is frequently
inactivated in tumor cells. Thus in BE, 4n/4C/G1 cells with mutated p53 and p16[ink4a]
genes gained cycling ability to tetraploid aneuploid cell cycles, which constituted
the change from hyperplasia to dysplastic lesions. In general, such lesions
have high predictive value for a cancerous change. Proliferation rates of
pre-neoplasia and progression have been shown to be increased by a component of
the wound healing program.