Stem Cell Stages and the Origins of Colon Cancer: A Multidisciplinary Perspective

Abstract

Analysis of historical age-specific colorectal cancer rates, present day age-specific colonic adenoma prevalence and the few reports of direct measurements of genetic change in human tissues as a function of age in adults have led to a new set of hypotheses about carcinogenesis. A key observation, that the calculated rate of growth of preneoplasia is equal to the calculated growth rate of the juvenile colon, suggested that tumor initiation blocks the developmental step by which growing juvenile stem cells are transformed into or replaced by adult maintenance stem cells. In this hypothesis the slowly growing adenomatous polyps would simply be patches of highly organized juvenile tissue modified by the mechanical constraints of surrounding nongrowing adult tissue. As juvenile tissue presumably grows by net increase in stem cells creating crypts, tumor promotion could be achieved by transformation of an initiated stem cell into a fetal stem cell that would express the program of rapid net growth and differentiation into the heterogeneous cell types of fetal colonic organogenesis. (One additional interpretation of data from observations of point mutations in adult lung epithelium is that rates of genetic change in juvenile stem cells are markedly higher than in adult maintenance stem cells.) Unfortunately, the concept of a "stem cell" undergoing staged transitions in organ development and blocked or reverse transitions in carcinogenesis has lacked the physical embodiment of a cell that could be recognized, isolated, and analyzed. In an attempt to overcome this impediment we set reexamined fetal and adult colonic tissue, adenomas, and adenocarcinomas using a novel histological preparation method. Gostjeva then discovered that fetal and neoplastic tissues share a set of cells distinguished by specific nuclear morphotypes that appear to cooperate in creating the elements of the fetal organ, preneoplastic, and neoplastic lesions. In particular, microscopic examination of fetal gut at 5-7 wk gestation reveals tubular syncytia containing opened-mouthed, bell-shaped nuclei that account for some 30% of the nuclei in the protoorgan. These peculiar nuclei undergo both symmetric and asymmetric nuclear fissions, the latter creating all of the other nuclear morphotypes. These nuclear fissions are "amitotic" insofar as no general chromosome condensation is observed. Bell-shaped nuclei are rarely found in adult colonic crypt bases but are found in preneoplasia and neoplasia.

Comparison of Oct4, Sox2 and Nanog Expression in Pancreatic Cancer Cell Lines and Human Pancreatic Tumor

“…Today, the genes that are involved in stem cell self-renewal have been introduced as a new class of molecular markers of cancer that play important role in the uncontrolled proliferation of cancer cells (28,29).…”

Human fetal/tumor metakaryotic stem cells: pangenomic homologous pairing and telomeric end-joining of chromatids

“…Search of the cytogenetic literature has failed to discover a previous report of any cell type with centromeric and telomeric pairing and all telomeric sequences apparently involved in end-to-end junctions. Taken together with the quantitative cytometric evidence of amitotic fission [2, 3] of the bell shaped nuclei, DNA doubling occurring during and soon after nuclear fission [3] and images of clear asymmetric amitotic fissions creating the mitotic eukaryotic forms of various tissue parenchyma [1–3], these data establish these putative stem cells as “metakaryotic” organisms with modes of genomic organization, DNA segregation and replication distinct from eukaryotic cells.…”

“…Feulgen DNA image cytometry reveals that bell shaped nuclei increase by either of two forms of symmetrical amitoses concomitant with DNA doubling without chromosomal condensation. Furthermore, cells with bell-shaped nuclei undergo asymmetric amitoses to create a diverse set of cells with at least nine distinguishable nuclear morphotypes including those of the fetal and tumor parenchymal cells that subsequently increased in number by mitoses [1, 2, 3]. …”

“…Because of marked differences between these previously unreported nuclear forms and eukaryotic nuclei in size, shape, DNA synthesis and segregation these cells have been denominated metakaryotes [1, 2]. The cytological evidence of asymmetric nuclear fissions creating specific nuclear morphotypes of cells that subsequently divide by mitosis and comprise the fetal/juvenile tissue or tumor parenchyma supports the hypothesis that cells with bell shaped nuclei comprise a stem cell lineage in organogenesis and carcinogenesis.…”

Metakaryotic stem cell nuclei use pangenomic dsRNA/DNA intermediates in genome replication and segregation

“…The cytological evidence of asymmetric nuclear fissions creating cells with eukaryotic nuclei that increase by mitoses to define the fetal/juvenile tissue or tumor parenchyma in humans supported the inference that cells with bell shaped nuclei comprise a stem cell lineage in organogenesis and carcinogenesis 1 , 2 . The nuclear bell shapes and arrays of eukaryotic nuclear forms seen in adenomatous and mesenchymal tumor areas are not easily distinguished from those in developing fetal organs of the second trimester 1 - 3 .…”