Biochemical markers associated with the stages of promotion and progression during hepatocarcinogenesis in the rat.

Pitot, Henry C.; Dragan, Yvonne P.; Sargent, Linda M.; Xu, Yijia

doi:10.1289/ehp.9193181

Cited by 31 publications

(11 citation statements)

References 48 publications

(52 reference statements)

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“…The observed number of promoter-independent AHF per liver differed significantly from that observed for animals in which no second initiator was administered (P c 0.05) (adapted from Pitot et a/. [19]). [19]).…”

Section: Resultsmentioning

confidence: 77%

“…Morphologically, the earliest detectable lesion after administration of the progressor agent in the IPP protocol may be the "focus-in-focus" as described by Scherer ( 15,16,18) and Pitot (1 7,25) and his colleagues (19,43). The detection of a focus-infocus (FIF) is dependent upon the growth rate and morphology of the second (internal) focus and is dificult for single phenotypes; however, it may be possible to use the overlays of focal transections obtained for different enzyme markers on serial sections to identify phenotypically distinct, smaller, and presumably more recent lesions (FIF) within larger, presumably older ones (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Treatment of animals on the IPP protocol with a partial hepatectomy 6 months after beginning the promotion regimen, but with subsequent removal of the promoting agent, resulted in a basal level of promoter-independent foci ([PIF] Table I). Table I shows that treatment with either HU or ENU after the partial hepatectomy resulted in a significantly greater number of PIF than observed in animals not receiving a putative progressor agent (19). a Data are the numbers of promoter-independent (i.e., progressed) AHF per liver determined by quantitative stereology for animals (7-12 female Sprague-Dawley rats) treated on an IPP protocol (see Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The rat liver model of cancer development has played an important role in our understanding of the processes involved and the changes that accompany preneoplasia all phases of neoplastic development after initiation. The demonstration of an operationally reversible, intermediate stage of promotion that is dependent upon the continued administration of the promoting agent and that does not involve demonstrable changes in the genome (19) suggests that Foulds' concept of progression should be reevaluated. Since promotion, if existent, immediately follows initiation, progression can be considered the terminal stage of neoplastic development…”

mentioning

confidence: 99%

“…The initiation-promotion-progression (IPP) protocol of chemical carcinogenesis was suggested by Potter (9) and has been used to demonstrate the ability of complete carcinogens ( 10, 1 1, 14), selectively cytotoxic agents ( 12), and free radical generators (1 3) to induce progression in the mouse skin model. The IPP protocol also models these three stages in the rat liver (1 8, 19, 25, 26) and, coupled with the technique of quantitative stereology, permits the investigation of each stage separately (19,25,26). Several phenotypic markers of altered hepatic foci have been used in two morphologic methods of assessing progressor action.…”

mentioning

confidence: 99%

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The Initiation-Promotion-Progression Model of Rat Hepatocarcinogenesis

Dragan¹,

Sargent²,

Xu³

et al. 1993

Experimental Biology and Medicine

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Carcinogenesis is a multistage process consisting of the three distinct stages: initiation, promotion, and progression. The initiation-promotion-progression (IPP) protocol models these stages and establishes a method whereby agents that possess a carcinogenic risk can be classified as acting primarily at any one or combination of these stages. In one hepatocarcinogenesis IPP protocol, rats were initiated with 10 mg of diethylnitrosamine/kg body wt at 5 days of age, started on the promoting agent phenobarbital at weaning, subjected to a 70% partial hepatectomy at 6 months, and, at the peak of proliferation, given a putative progressor agent, ethylnitrosourea ([ENU] 100 mg/kg, ip) or hydroxy-urea ([HU] 3 x 150 mg/kg, ip). Administration of the promoting agent was discontinued after the progressor agent was given, and the rats were sacrificed 6 months later. The number and volume fraction of promoter-independent (growth in the absence of the promoting agent) altered hepatic foci (AHF) were then determined by quantitative stereology. The number of such AHF increased with either ENU or HU treatment compared with animals not given a progressor agent. In addition, hepatocytes isolated from animals subjected to an IPP regimen with ENU as the progressor agent exhibited a greater degree of chromosomal breakage and aneuploidy than animals not given a second initiator. A variation of this model, in which the promoting agent was maintained after administration of the progressor agent, was examined. In this IPP model, the number of heterogeneous AHF (foci-in-foci) increased after application of the progressor agent (ENU or HU). An increased incidence of hepatocellular carcinoma was also observed in animals subjected to the IPP protocol when promotion was maintained until sacrifice. Thus, the characteristics of progression--increased chromosomal damage, aneuploidy, growth of AHF in the absence of continued tumor promotion, the presence of foci-in-foci, and an increased incidence of malignant neoplasia--have been used as end points for the demonstration of progressor activity by ENU. In addition, the potential progressor activity of HU and benzene has been demonstrated with the IPP model of rat hepatocarcinogenesis.

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Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Initiation-Promotion-Progression Model of Rat Hepatocarcinogenesis

Dragan¹,

Sargent²,

Xu³

et al. 1993

Experimental Biology and Medicine

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A new mechanism of cancer initiation that involves the transformation of hepatocytes into preneoplastic single hepatocytes and minifoci positive for glutathione S‐transferase P‐form (GST‐P) in rat livers: 3D analysis using a vibratome

Satoh

2024

Cancer Medicine

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BackgroundCancer initiation has long been “unknowable” in biology and medicine. In 1987, however, Moore and our research group observed single hepatocytes and minifoci that were strongly positive for glutathione S‐transferase P‐form (GST‐P) in the rat liver as early as 2 to 3 days after initiation by diethylnitrosamine prior to the induction of GST‐P+ foci and nodules. The induction of GST‐P+ single hepatocytes, precursors of GST‐P+ foci and nodules, was considered genetic. But, the details of the induction mechanism have remained unclear despite various examinations over a long period.MethodsMale Sprague‐Dawley rats (aged 6 weeks) were fed a basal diet containing either benzyl isothiocyanate (BITC, 0.5% by wt) or 2‐acetylaminofluorene (AAF, 0.04%) ad libitum for appropriate time intervals. All animals were anesthetized and euthanized. The livers obtained were excised, cut into 3‐ to 4‐mm‐thick slices and fixed in cold acetone at 4 °C. The liver specimens were then sliced into 25‐µm‐thick sections in PBS using an automated microtome (Vibratome 1500 Sectioning System, Vibratome Products, NY, USA). Immunocytochemical staining was performed in free solution, and the results were examined via digital light microscopy (Coolscope, Nikon, Tokyo).Results3D analysis using a vibratome showed that GST‐P is rapidly excreted into the bile of the liver of animals in response to strong carcinogenic stress caused by promoters or initiators. “Rapid biliary excretion of GST‐P” was widely and commonly observed in all hepatocytes, GST‐P+ single hepatocytes, minifoci, foci and nodules under appropriate conditions. Surprisingly, on the basis of these key findings, a new mechanism of cancer initiation involving the transformation of hepatocytes into GST‐P+ single hepatocytes and minifoci in animal livers was identified. In addition, the initiation process was determined to be nongenetic because mutation is an invisible rare event.ConclusionsThis short review describes several details about breakthrough findings on cancer initiation in rat livers, the application of 3D analysis to other cancers and the importance in the genetic analysis in malignant diseases.

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Thyroid hormone receptor ligands induce regression of rat preneoplastic liver lesions causing their reversion to a differentiated phenotype #

et al. 2009

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Triiodothyronine (T3), through interaction with its intracellular thyroid hormone receptors (TRs), influences various physiological functions, including metabolism, development, and growth. We investigated the effect of T3 and the selective TR-␤ agonist GC-1 in two models of hepatocarcinogenesis. Preneoplastic lesions were induced in F-344 rats via a single dose of diethylnitrosamine, followed by a choline-deficient (CD) diet for 10 weeks. Rat subgroups were then fed the CD diet or a CD diet containing either 4 mg/kg T3 or 5 mg/kg GC-1 for another week. Rats fed a CD diet alone showed a large number (65/cm 2 ) of preneoplastic lesions positive for the placental form of glutathione S-transferase (GSTP). Coadministration of T3 for the last week caused an almost complete disappearance of the foci (3/cm 2 ). A reduction of GSTP-positive foci was also observed in rats fed a CD ؉ GC-1 diet (28/cm 2 versus 75/cm 2 of rats fed a CD diet alone) in the absence of significant differences in labeling or apoptotic index of preneoplastic hepatocytes between the two groups. An antitumoral effect of GC-1 was also observed with the resistant hepatocyte model of hepatocarcinogenesis. Nodule regression was associated with a return to a fully differentiated phenotype, indicated by the loss of the fetal markers GSTP and gamma glutamyl transpeptidase, and reacquisition of the activity of glucose 6-phosphatase and adenosine triphosphatase, two enzymes expressed in normal hepatocytes. Conclusion: Our results indicate that activated TRs negatively influence the carcinogenic process through induction of a differentiation program of preneoplastic hepatocytes. The results also suggest that TRs could be a meaningful target in liver cancer therapy. (HEPATOLOGY 2009;49:1287-1296

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Biochemical markers associated with the stages of promotion and progression during hepatocarcinogenesis in the rat.

Cited by 31 publications

References 48 publications

The Initiation-Promotion-Progression Model of Rat Hepatocarcinogenesis

The Initiation-Promotion-Progression Model of Rat Hepatocarcinogenesis

A new mechanism of cancer initiation that involves the transformation of hepatocytes into preneoplastic single hepatocytes and minifoci positive for glutathione S‐transferase P‐form (GST‐P) in rat livers: 3D analysis using a vibratome

Thyroid hormone receptor ligands induce regression of rat preneoplastic liver lesions causing their reversion to a differentiated phenotype #

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