Phase 1 and phase 2 proliferative lesions of colonic epithelial cells in diseases leading to colonic cancer

Abstract

Colonic epithelial cells in man begin to develop some of the characteristics of malignant cells while they still appear normal on conventional morphological examination. The cells pass through specific phases during which they express increasingly abnormal proliferative characteristics. As a Phase 1 proliferative lesion develops, colonic epithelial cells do not repress DNA synthesis during their maturation, and begin to develop an enhanced ability to proliferate. The over‐all kinetics of cell proliferation remain normal, without a net retention or accumulation of cells in the mucosa. As a Phase 2 proliferative lesion forms, the cells begin to develop properties that enable them to be retained in the mucosa in increasing numbers. The over‐all kinetics of cell proliferation become abnormal, and net retention and accumulation of cells begin to be observed. These changes are accompanied by differentiation‐specific molecular errors, resulting in the abnormal persistence of metabolic pathways leading to enhanced DNA synthesis. These proliferative cellular lesions arise in hereditary familial polyposis in man, in individuals in the general population who develop isolated colonic neoplasms, and in rodents after a chemical carcinogen is given, suggesting that they are major steps on a final common molecular pathway leading to malignant transformation. Their expression is accelerated in familial polyposis. The proliferative lesions and increasingly severe degrees of cellular atypia can be screened in familial polyposis, the utility of the screening procedure is being studied. The molecular lesions leading to persistent DNA synthesis, the interaction of suspected carcinogens leading to the appearance of the above changes in model systems, and the development of more effective chemotherapy and immunotherapy against the reactions leading to enhanced DNA synthesis are topics of importance at the present time.

Mucous secretion in rat colonic mucosa during carcinogenesis induced by dimethylhydrazine. A morphological and histochemical study

“…The mechanism of action of DMH is not yet fully understood but it may interact with nucleic acids and/or protein (Miller and Miller, 1966;Shank and Magee, 1967;Farber, 1968) and thus alter the normal process of cell differentiation and maturation. Indeed, Lipkin and co-workers have described changes in the nucleic acid metabolism and proliferative capacity of the colonic epithelium in DMH treated mice (Thurnherr et al, 1973;Deschner, 1974) which are similar to those found in the human colonic mucosa adjacent to carcinoma and neoplastic polyps (Immondi, Balis and Lipkin, 1969;Deschner and Lipkin, 1970;Troncale, Hertz and Lipkin, 1971) and in familial polyposis (Lipkin, 1974). These changes may reflect a loss of suppressor genes and a regression of the cell to a more embryonic state, a hypothesis supported in the demonstration of embryonic specific antigens in malignant tumours (Gold and Freedman, 1965;von Kleist and Burtin, 1969;Stonehill and Bendich, 1970;von Kleist, 1971;Bordes, Michiels and Martin, 1973).…”

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

“…2). Thus, the acute enhancement of DNA synthesis induced by cyclooxygenase inhibitors appears to occur mainly in the lower third of the crypt, the region that normally demonstrates proliferative activity (27). The small increase in [3H]dThd incorporation observed in the superficial cell isolates may be due to minor contamination of this pool with proliferative cells from the lower zones.…”

Hereditary nonpolyposis colorectal cancer (lynch syndromes I and II). II. Biomarker studies

“…Three maximum likelihoods were calculated for each trait: ( 1 ) with the transmission probabilities constrained to be Mendelian; (2) with the transmission probabilities constrained to be equal: and (3) under the unrestricted model of arbitrary (but between 0 and 1) transmission probabilities. Each of the first two likelihoods was compared with the third likelihood to obtain an asymptotic chi-square test of significance.…”