title: The inhibitory effect of rapamycin on the oval cell response and development of preneoplastic foci in the rat.
abstract: Oval cell activation occurs under conditions of severe liver injury when normal hepatocyte proliferation is blocked. Recent studies have shown that a subset of hepatocellular carcinomas expresses oval cell markers, suggesting that these cells are targets of hepatocarcinogens. However, the signaling pathways that control oval cell activation and proliferation are not well characterized. Based on the role of the nutrient signaling kinase complex, mTORC1, in liver development, we investigated the role of this pathway in oval cell activation. Oval cell proliferation was induced in male Fisher rats by a modification of the traditional choline deficient plus ethionine model (CDE) or by 2-acetylaminoflourene treatment followed by 2/3 partial hepatectomy with or without initiation by diethylnitrosamine. To assess the role of mTOR in the oval cell response and development of preneoplastic foci, the effect of the mTORC1 inhibitor, rapamycin, was studied in all models. Rapamycin induced a significant suppression of the oval cell response in both models, an effect that coincided with a decrease in oval cell proliferation. Rapamycin administration did not affect the abundance of neutrophils or natural killer cells in CDE-treated liver or the expression of key cytokines. Gene expression studies revealed the fetal hepatocyte marker MKP-4 to be expressed in oval cells. In an experimental model of hepatic carcinogenesis, rapamycin decreased the size of preneoplastic foci and the rate of cell proliferation within the foci. mTORC1 signaling plays a key role in the oval cell response and in the development of preneoplastic foci. This pathway may be a target for the chemoprevention of hepatocellular carcinoma.
authors.affiliation: Department of Pediatrics, Division of Endocrinology and Metabolism, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903 USA. Jennifer_Sanders@brown.edu
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sanders
authors.forename: Kate E
authors.initials: KE
authors.lastname: Brilliant
authors.forename: Danielle
authors.initials: D
authors.lastname: Clift
authors.forename: Ajay
authors.initials: A
authors.lastname: Patel
authors.forename: Bruno
authors.initials: B
authors.lastname: Cerretti
authors.forename: Patricia
authors.initials: P
authors.lastname: Claro
authors.forename: David R
authors.initials: DR
authors.lastname: Mills
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Hixson
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gruppuso
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D002796:Choline Deficiency / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis; D005001:Ethionine / Q000633:toxicity; D005449:Fluorenes / Q000633:toxicity; D020869:Gene Expression Profiling; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000096:biosynthesis; D046912:Multiprotein Complexes; D011230:Precancerous Conditions / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D005449:Fluorenes; D046912:Multiprotein Complexes; D011506:Proteins; C012177:2-aminofluorene; D004052:Diethylnitrosamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C574490:Dusp9 protein, rat; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; D020123:Sirolimus; D005001:Ethionine