Journal Article

Quantitative analysis of tumor initiation in rat liver: role of cell replication and cell death (apoptosis)

Bettina Grasl-Kraupp, Georg Luebeck, Alexandra Wagner, Alexandra Löw-Baselli, Mathisca de Gunst, Thomas Waldhör, Suresh Moolgavkar and Rolf Schulte-Hermann

in Carcinogenesis

Volume 21, issue 7, pages 1411-1421
Published in print July 2000 | ISSN: 0143-3334
Published online July 2000 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/21.7.1411
Quantitative analysis of tumor initiation in rat liver: role of cell replication and cell death (apoptosis)

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The formation and development of initiated cells has been studied at the beginning of hepatocarcinogenesis. Rats received the genotoxic carcinogen N-nitrosomorpholine (NNM); placental glutathione S-transferase was used as a marker of initiated cells (G+ cells). Single G+ cells appeared within 24 h after NNM; their frequency increased steeply for ~2 weeks, then decreased and finally remained constant. G+ foci consisting of ≥2 G+ cells appeared successively after the single cells. Histological determination of DNA replication and apoptosis revealed that: the formation of single G+ cells may not depend on DNA replication of precursor cells; single G+ cells showed considerably lower DNA replication than G– normal hepatocytes; from the 2-cell stage onwards G+ foci displayed enhanced DNA replication and apoptosis. Data from histological sections were transformed into the third dimension by a new stereological method which considers the non-spherical shape of many G+ lesions. Rates of division and death of G+ cells and of formation and growth of G+ foci were estimated by a stochastic model: initially G+ clones appeared at a rate of 12 000 per day and liver until a maximal number of 176 000 (phase I) was reached; thereafter they declined to 134 000 (phase II); they then remained constant (phase III). Estimated division rates of G+ cells decreased from phase I to phase III, while the death rate increased in phase II, when every third G+ clone disappeared. As a result, at day 50 after NNM only 0.3% of G+ single cells had formed a clone containing ≥5 cells. In conclusion, experimental and computed parameters provide direct evidence that hepatocarcinogenesis evolves clonally and that initiated hepatocytes have a selective proliferation advantage, associated with an enhanced potential to undergo apoptosis. Thereby, depending on the conditions, initiated clones expand or become extinct. Extinction may lead to reversion of the biological effects of initiation.

Keywords: 2D, two-dimensional; 3D, three-dimensional; AB, apoptotic body; AI, apoptotic body index; CI, confidence interval; G+, placental glutathione S-transferase-positive; G–, placental glutathione S-transferase-negative; GLDH, glutamate dehydrogenase; GST-P, placental glutathione S-transferase; LI, labeling index; NNM, N-nitrosomorpholine.

Journal Article.  9990 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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