Delineation of antigenic pathways of ethionine-induced liver cancer in the rat.
Although oval cell proliferation is observed prior to the appearance of hepatic nodules and hepatocellular carcinomas during ethionine-induced liver carcinogenesis in the rat, the role of these presumptive hepatic stem cells during the neoplastic process remains controversial. In order to investigate this question, we have used a panel of monoclonal antibodies against antigens associated with normal hepatocytes, oval cells and transplantable hepatocellular carcinomas (THC) to trace antigenic pathways leading to liver cancer. Male ACI rats were fed a choline-deficient diet containing 0.1% DL-ethionine for 4, 16 or 30 weeks. Immunocytochemical analysis of frozen liver sections revealed a subpopulation of hepatic nodules (7/52), carcinomas (8/15) and lung metastases (3/5) containing populations of cells expressing both oval cell, hepatocyte and neoplastic markers. Carcinomas expressing oval cell markers often appeared as a mosaic of well-defined patches composed of phenotypically distinct cells. Many of the phenotypes expressed closely mimicked patterns of expression observed in fetal and neonatal liver. THC derived from primary tumors positive for oval cell antigens (4/5) continued to express these markers. Northern blot analysis and immunocytochemical analysis revealed that 4/5 primary hepatocellular carcinomas (PHC) and THC expressed alpha-fetoprotein (AFP) and albumin transcripts and contained subpopulations expressing AFP together with hepatocyte and oval antigens. In contrast, a well-differentiated PHC and its corresponding THC lacked AFP mRNA and oval cell antigens but showed strong expression of both hepatocyte and neoplastic markers. These results demonstrate that a subpopulation of malignant and metastatic hepatocellular carcinomas are comprised of cells expressing multiple oval cell markers in this model system.
Department of Medical Oncology, Rhode Island Hospital-Brown University, Providence 02902, USA.
D C
DC
Hixson
S
S
Affigne
R A
RA
Faris
A C
AC
McBride
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis*; D001652:Bile Ducts / Q000276:immunology; D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000276:immunology; D002277:Carcinoma / Q000276:immunology / Q000556:secondary*; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D056486:Chemical and Drug Induced Liver Injury; D002796:Choline Deficiency / Q000150:complications; D005001:Ethionine / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000276:immunology; D008107:Liver Diseases / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary*; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology; D010641:Phenotype; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D011912:Rats, Inbred ACI; D013234:Stem Cells / Q000276:immunology* / Q000473:pathology; D000509:alpha-Fetoproteins / Q000096:biosynthesis / Q000276:immunology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000509:alpha-Fetoproteins; D005001:Ethionine