Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments—I. Single agent regimen

Moolgavkar, Suresh H.; Luebeck, E. Georg; Gunst, Mathisca de; Port, Ruediger E.; Schwarz, Michael

doi:10.1093/carcin/11.8.1271

Cited by 105 publications

(31 citation statements)

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“…Coinciding with regenerative DNA synthesis, there was a dramatic increase of GST-P positive single cells and mini-foci, which after a plateau declined and finally reached approximately 20% of the peak value. Although there is no absolute proof that GST-P positive cells are truly initiated and that they only disappear through apoptosis, these observations fit well the mathematical predictions (13). A similar decline of GST-P positive cells has also been observed by Satoh et al (16) in a study with diethylnitrosamine.…”

Section: Role Of Cell Replication and Apoptosis In Multistep Chemicalsupporting

confidence: 85%

Cell Proliferation and Apoptosis in Normal Liver and Preneoplastic Foci

Schulte‐Hermann¹,

Bursch²,

Kraupp-Grasl³

et al. 1993

Environmental Health Perspectives

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The growth rate of tissues including tumors is determined by the difference between cell replication and cell death. Among different types of cell death, apoptosis, a form of programmed cell death, is of particular importance. Nongenotoxic carcinogens exert their carcinogenic effects not only via stimulation of cell replication but also by modulating the incidence of apoptosis. This can be seen at different stages of carcinogenesis: a) After initiation in the liver, many initiated cells may undergo apoptosis and never develop into preneoplastic foci, as suggested by both biological and mathematical studies. Thus, apoptosis appears to determine the efficiency of initiation. b) In the promotion stage, early preneoplastic hepatic foci originate either from treatment with a genotoxic carcinogen or spontaneously exhibit much higher rates of cell replication than normal cells, but nevertheless show little preferential growth. This is due to enhanced rates of apoptosis. Some tumor promoters were found to inhibit apoptosis and thereby accelerate foci growth and carcinogenesis. c) In neoplastic nodules and tumors, apoptosis has been shown to be an important growth determinant and to be regulated by growth regulatory hormones, which thereby may decrease or accelerate tumor growth. Studies on the regulation of apoptosis revealed that in the liver, transforming growth factor TGF-01 is involved in the initiation of apoptosis. This was based on three lines of evidence: TGF-fi1 induced apoptosis in isolated hepatocytes, b) in vivo hepatocytes undergoing apoptosis showed positive immunostaining with antibodies against a precursor of TGF-i1. This staining response was not seen in normal or necrotic hepatocytes, c) injection of TGF-I1 into intact animals induced apoptosis in the liver in vivo.

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Section: Role Of Cell Replication and Apoptosis In Multistep Chemicalsupporting

confidence: 85%

Cell Proliferation and Apoptosis in Normal Liver and Preneoplastic Foci

Schulte‐Hermann¹,

Bursch²,

Kraupp-Grasl³

et al. 1993

Environmental Health Perspectives

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“…A stochastic birth process was implemented to model the size distributions of clones that grow exponentially at rate ␣ (38). The probability that a clone at time t contains z cells is:…”

Section: Exponential Growth Modelmentioning

confidence: 99%

Preneoplastic lesion growth driven by the death of adjacent normal stem cells

Chao

Eck

Brash

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Clonal expansion of premalignant lesions is an important step in the progression to cancer. This process is commonly considered to be a consequence of sustaining a proliferative mutation. Here, we investigate whether the growth trajectory of clones can be better described by a model in which clone growth does not depend on a proliferative advantage. We developed a simple computer model of clonal expansion in an epithelium in which mutant clones can only colonize space left unoccupied by the death of adjacent normal stem cells. In this model, competition for space occurs along the frontier between mutant and normal territories, and both the shapes and the growth rates of lesions are governed by the differences between mutant and normal cells' replication or apoptosis rates. The behavior of this model of clonal expansion along a mutant clone's frontier, when apoptosis of both normal and mutant cells is included, matches the growth of UVB-induced p53-mutant clones in mouse dorsal epidermis better than a standard exponential growth model that does not include tissue architecture. The model predicts precancer cell mutation and death rates that agree with biological observations. These results support the hypothesis that clonal expansion of premalignant lesions can be driven by agents, such as ionizing or nonionizing radiation, that cause cell killing but do not directly stimulate cell replication.clonal expansion ͉ computer simulation ͉ skin cancer ͉ TP53 ͉ UVB

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“…In the present study, the area fraction of GSTP-positive foci in liver increased ∼linearly with NNM dose. Modeling of data on the evolution of FAH in liver of rats 76 ITTRICH ET AL TOXICOLOGIC PATHOLOGY chronically exposed to varying dose-levels of NNM demonstrated a close to linear dose-response for both initiating and promoting activity of the agent, with initiating activity exceeding by far the promoting activity (38). 2-Acetylaminofluorene: 2-AAF is a prototype carcinogenic aromatic amine.…”

Section: Discussionmentioning

confidence: 99%

“…The extrapolation of the number and size of FAH from observations in 2 to 3 dimensions, however, is not straightforward, due to potential pitfalls related to the stereological proceduces commonly used (31,33). Mathematical modeling using biologically based hypotheses may offer a very useful tool allowing estimations on the rate of the transition of preneoplastic cells from normal cells, their net growth rate and their rate of death (34,38).…”

Section: Introductionmentioning

confidence: 99%

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

et al. 2003

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A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.

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Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments—I. Single agent regimen

Cited by 105 publications

References 0 publications

Cell Proliferation and Apoptosis in Normal Liver and Preneoplastic Foci

Cell Proliferation and Apoptosis in Normal Liver and Preneoplastic Foci

Preneoplastic lesion growth driven by the death of adjacent normal stem cells

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

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