Vibratome technique revealed initial carcinogenic changes that induce GST-P(+) single hepatocytes and minifoci in rat liver.

The drastic initial carcinogenic changes that induce single hepatocytes and minifoci positive for GST-P (a specific biomarker of foci and nodules) identified previously in rat livers (K. Satoh, Life Sci. 2018) require elucidation. Notably, after animals were administered benzyl isothiocyanate (BITC, anti-cancer phytochemical, 0.5% by wt) in their basal diet, immunocytochemical staining of vibratome-prepared liver specimens for GST-P revealed that the canalicular networks and bile ducts of the animal livers were heavily and finely stained for GST-P even though the biomarker is a cytosolic enzyme. In addition, the mean diameter of the canaliculi was greatly enlarged. The results thus indicate that GST-P was rapidly synthesized in all hepatocytes but rapidly excreted into bile. Similar results were obtained with animals administered dietary AAF carcinogen (0.04%). The biliary excretion of GST-P was detectable not only in all hepatocytes but also within minifoci, foci and nodules. A new initiation model was therefore proposed assuming that GST-P+ single hepatocytes are formed after injury to canaliculi by carcinogens to decrease the excretion of GST-P from hepatocytes. The key findings from this study and the biomarker analysis using a vibratome technique might help elucidate the 'unknowable' mechanism of cancer initiation in rat chemical carcinogenesis.

Satoh K ，Yamakawa D ，Kasai K ，Hatayama I ... -  《-》

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 K 《Cancer Medicine》

Strong carcinogenic stress response induction of preneoplastic cells positive for GST-P in the rat liver: Physiological mechanism for initiation.

To identify experimental conditions that induce preneoplastic cells positive for glutathione S-transferase P-form (GST-P) in the rat liver by new approaches, and analysis of the mechanism of cancer initiation based on the findings. The experimental protocols employed to induce GST-P+ preneoplastic cells in rat liver were as follows. Protocol 1: adult rats were fed basal diet containing 2-acetylaminofluorene (AAF, 0.02% by wt) and high concentrations of N-acetyl-l-cysteine (0.5%) over 10 weeks. Protocol 2: rats were subjected to partial hepatectomy (2/3PH), followed by an AAF (0.04%) diet for two more weeks. Vibratome-prepared liver sections were then immunostained for GST-P. GST-P was inducible in the rat liver in response to the strong carcinogenic stress by AAF in the two experimental protocols. When examined immunocytochemically with vibratome sections, the biliary tracts of hepatocytes, GST-P+ single hepatocytes and foci were heavily positive for the marker enzyme in addition to ordinary cytosolic staining of preneoplastic cell populations. The biliary tracts of hepatocytes were severely injured, and the excretory portions of GST-P+ single hepatocytes were significantly injured. The cytotoxic action of AAF that give rise to the GST-P+ single hepatocytes was suggested to be an injury to the excretory pump(s) and the duct of hepatocytes. A new physiological mechanism was hypothesized for the induction of preneoplastic cell populations in the rat liver instead of a genetic mechanism.

Satoh K 《-》

Bile duct-bound growth of precursor cells of preneoplastic foci inducible in the initiation stage of rat chemical hepatocarcinogenesis by 2-acetylaminofluorene.

Satoh K ，Yamakawa D ，Sugio H ，Kida K ，Sato T ，Hosoi K ，Hayakari M ... -  《-》

Effect of cell proliferation on initiation of aflatoxin B1-induced enzyme altered hepatic foci in rats and hamsters.

Hiruma S ，Qin GZ ，Gopalan-Kriczky P ，Shinozuka H ，Sato K ，Lotlikar PD ... -  《CARCINOGENESIS》