Stem cell stages and the origins of colon cancer: a multidisciplinary perspective.

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.