New principle for the analysis of chemical carcinogenesis

Solt, Dennis B.; Farber, Emmanuel

doi:10.1038/263701a0

Cited by 726 publications

(312 citation statements)

References 6 publications

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“…Their distribution seemed to be random on traditional sections and were surrounded by the rest of the oval cells. This latter histological reaction is almost identical with early events of the Solt-Farber hepatocarcinogenesis model, 10 where the foci are supposed to be putative, clonal tumor precursor lesions, which derive from the initiated hepatocytes. 11 The AAF-PH model does not lead to tumor formation; apparently, the normal architecture is reestablished in a few weeks.…”

supporting

confidence: 65%

“…This protocol is one of the most widely analyzed chemical hepatocarcinogenesis models, called the Solt-Farber or resistant hepatocyte model. 10,11 Using this carcinogenic protocol, the analysis of the foci could not reveal any difference to the foci developed without DEN treatment. The foci of the Solt-Farber model were also arranged around the terminal branches of the portal veins, whereas the central veins were pushed aside (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…Diethyl nitrosamine (DEN) (200 mg/kg) was intraperitoneally injected into rats. 10 Two weeks later, the AAF-PH protocol was performed as described above.…”

Section: Methodsmentioning

confidence: 99%

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Structural analysis of oval-cell–mediated liver regeneration in rats

et al. 2012

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We have analyzed the architectural aspects of progenitor-cell-driven regenerative growth in rat liver by applying the 2-acetaminofluorene/partial hepatectomy experimental model. The regeneration is initiated by the proliferation of so-called oval cells. The oval cells at the proximal tips of the ductules have a more differentiated phenotype and higher proliferative rate. This preferential growth results in the formation of a seemingly random collection of small hepatocytes, called foci. These foci have no clonal origin, but possess a highly organized structure, which shows similarities to normal hepatic parenchyma. Therefore, they can easily remodel into the lobular structure. Eventually, the regenerated liver is constructed by enlarged hepatic lobules; no new lobules are formed during this process. The foci of the Solt-Farber experimental hepatocarcinogenesis model have identical morphological features; accordingly, they also represent only regenerative, not neoplastic, growth. Conclusion: Progenitor-cell-driven liver regeneration is a well-designed, highly organized tissue reaction, and better comprehension of the architectural events may help us to recognize this process and understand its role in physiological and pathological reactions. (HEPATOLOGY 2012;56:1457-1467 T here are several alternative mechanisms of liver regeneration. 1 Hepatocytes can enter the cell cycle or enlarge, and the consequent compensatory hyperplasia or hypertrophy replaces the lost liver mass. We have demonstrated that new hepatic lobules are not formed during this type of regeneration, but the remaining lobes grow exclusively by the enlargement of preexistent hepatic lobules. 2 If the hepatocytes are compromised, the progenitor cell compartment is activated and the liver regenerates by means of the socalled oval cells in the rat. 3 Oval cells invade the liver parenchyma from the periportal region. They form ductules, which are the extensions of the canals of Hering. 4 The distribution of the differentiating cells can be different, depending on the species and etiology. In human liver, singular intermediate hepatobiliary cells can often be observed in proliferating ductules after extensive necrosis, 5 but small groups of differentiating cells are also described in chronic hepatitis and cirrhosis. 6,7 The 2-acetaminofluorene/partial hepatectomy (AAF-PH) model 8 is one of the most widely applied experiments to study oval cell proliferation and differentiation in rats. We characterized the differentiating progenitor cells in this experimental model. Two alternative patterns of differentiation were observed previously depending on the applied dose of AAF. 9 In the case of a low dose (2.5 mg/kg/day of AAF), differentiation occurred earlier and practically all the oval cells transformed into small, newly formed hepatocytes. If the dose of AAF was higher (5 mg/kg/ day of AAF), differentiation occurred later and involved only a small portion of oval cells. Sharply

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supporting

confidence: 65%

Section: Resultsmentioning

confidence: 89%

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Structural analysis of oval-cell–mediated liver regeneration in rats

et al. 2012

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“…It has been suggested that the increase in GGT activity in hepatocytes in vivo indicates the acquired resistance of these cells to the cytotoxic effects of the carcinogen (Solt & Farber, 1976;Tsuda et al, 1980), which in turn allows them to proliferate preferentially in the continuing presence of the carcinogen. It has already been shown that the JBI cells are more resistant to the cytotoxic action of AFB1 than the BL8L cells (Manson et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

Effect of microsomally activated AFB1 on GGT activity in 3 rat liver cell lines

Manson¹,

Green²

1982

Br J Cancer

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Summary.-Three cell lines derived from adult rat liver have been used to study changes in levels of y-glutamyl transferase (GGT), a possible marker for premalignant transformation in liver in vivo. None of the cell lines was able to metabolize aflatoxin B1 (AFB1) and treatment with AFB1 alone did not influence GGT activity. However, treatment with microsomally activated AFB1 increased the level of activity in a cell line (BL8L) derived from normal liver with very low levels of GGT, by as much as 10-fold, and 5-fold in a cell line (ARL) also isolated from normal rat liver, but which had subsequently undergone spontaneous transformation. Microsomes from rats pretreated with phenobarbitone were compared with those from 3-methylcholanthrene-treated animals. AFB1 activated by the former produced larger increases in GGT activity, but in no case did the enzyme levels approach that in a cell line (JBI) derived from a hepatoma in the liver of an AFB,-fed rat. Treatment of JBI cells with microsomally activated AFB1 produced no further increase in activity. Histochemical staining indicated an uneven distribution of enzyme in all cell populations, both before and after treatment. This cell-culture system is useful for further studies on the role of GGT in carcinogenesis.

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“…The differential resistance of carcinogen-altered cells to toxicity by carcinogens was the basis of a clonalselection theory of cancer (Prehn, 1964) and experimental support for these ideas has recently included the ability of carcinogen-altered cells to proliferate selectively in vivo in a carcinogen-induced, toxic environment (Solt & Farber, 1976). The experiments reported here show that hepatocytes from AAF-treated rats are resistant to the cytocidal effects of the anthracyclene antibiotic ADR at concentrations which are toxic to hepatocytes from normal rats.…”

Section: Disc T Ss1onmentioning

confidence: 99%