Hepatic preneoplasia induction in male Wistar rats: histological studies up to five months post treatment

Abstract

Background: Liver preneoplasia development in rats can be mimicked by an initiation-promotion model that induces the appearance of altered hepatocyte foci (FAH).Aims: We compare two initiation-promotion models to evaluate the presence of FAH or additional hepatic pathologies in which other organs were affected up to five month post treatment.Material and methods: FAH were induced in male adult Wistar rats with two doses of dietylnitrosamine (DEN, 150 mg/kg bw) followed by 4 doses per week (3 weeks) of 2-acetylaminofluorene (2-AAF, 20 mg/kg bw) or with one dose of DEN (200 mg/kg bw) followed by 2 doses per week (3 weeks) of 2-AAF. DEN 150, DEN 200 and control rats (received the vehicle of the drugs) groups were compared. Rats were euthanized immediately after the last dose of 2-AAF, at 3, 4 and 5 months (n = 3 for euthanasia times per group). Samples of livers, lungs, kidneys, pancreatic tissue and small bowel were processed for histological and immunohistochemical analysis.Results: FAH persisted for 5 months in all livers of the DEN groups. Three months after withdrawal of 2-AAF, one rat from DEN 150 group developed fibrosis and 5 months after 2-AAF removal another rat from the same group presented a microscopic hyperplastic nodule. Only the lungs had damages compatible with lesions induced by gavage-related reflux in DEN groups.Conclusion: We concluded that up to five month post treatments, FAH persisted in all the livers from DEN groups; livers from DEN 200 group showed no other hepatic lesions besides FAH, and only the lungs suffered pathological alterations in both treated groups.

Genetically Engineered Mouse Models of Liver Tumorigenesis Reveal a Wide Histological Spectrum of Neoplastic and Non-Neoplastic Liver Lesions

“…A total of 369 formalin-fixed paraffin embedded blocks (FFPE) from macroscopically detectable tumor nodules were obtained from five GEMM with genetic alterations in various oncogenic pathways. An AlbCre (Speer6-ps1 Tg(Alb-cre) 21 ) line was used to allow for conditional genetic manipulation. Animals were crossed in different combinations with animals with genetic modifications of the KRAS (Kras tm4 ), PTEN (Pten flox ), TGFβR2 (TGFβR2 tm1 ) and/or IDH1 (IDH1 tm2 )-allele.…”

“…Both circumstances might cause or support a weak rate of reproducibility of histopathological results published, even very frequently, in high ranking journals [11,20]. Chemically induced rodent models for liver tumorigenesis (especially the so-called Diethylnitrosamine DEN-models) are well characterized and present with a huge variety of proliferative liver lesions of both neoplastic and non-neoplastic origin [21][22][23]. The most widely accepted classification of proliferative and non-proliferative liver lesions originates from the INHAND consortium (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) [19].…”

First approaches for the transplantation of hepatocytes from Wistar rat preneoplastic livers into healthy recipients

“…The initiation stage was performed by the administration of two intraperitoneal necrogenic doses of the initiator agent DEN (150 mg/kg body weight), two weeks apart. Administration of the promoter drug 2-AAF (11,12) was performed one week after the last injection of DEN. The 2-AAF was dissolved in dimethyl sulfoxide and then suspended in corn oil to a final concentration of 8 mg/ml.…”