title: Sequential analysis of hepatic carcinogenesis: a comparative study of the ultrastructure of preneoplastic, malignant, prenatal, postnatal, and regenerating liver.
abstract: The objective of this study was to compare the fine structure of presumptive preneoplastic hepatocytes at various times during liver carcinogenesis with that of normal, developing, and regenerating liver and of hepatocellular carcinomas, using transmission and scanning electron microscopy. A new model of liver carcinogenesis was used in which several of the early steps are quite well synchronized. A single initiating dose of diethylnitrosamine induced isolated islands of altered hepatocytes. The cells were characterized by persistence of glycogen despite starvation, increase in smooth endoplasmic reticulum, and hypertrophic nucleoli. Following intense selection of the altered hepatocytes by dietary 2-acetylaminofluorene plus partial hepatectomy, the affected hepatocytes proliferated rapidly to produce basophilic foci. These early hyperplastic lesions revealed stellate-shaped dilated bile canaliculi lined by blebs and abnormally thick elongated microvilli, a decreased number of microvilli on the sinusoidal surface, a marked increase in smooth endoplasmic reticulum, large nucleoli, and bundles of pericanalicular microfilaments. A majority of the proliferating lesions reacquired a normal organizational pattern within several weeks after partial hepatectomy and could not be distinguished from normal liver. A small number continued to grow and become typical persistent hyperplastic nodules. These showed significant widening of intercellular spaces between hepatocytes, elongated microvilli over large regions of the cell surface, many invaginations of the cell membrane, and irregularly shaped bile canaliculi. Sequential changes in focal hyperplastic hepatocytes during carcinogenesis could be distinguished from normal, developing, and regenerating liver. The major differences involved the cell surfaces and cytoplasmic organelles. The findings are compatible with the hypothesis that a carcinogen may act by inducing alterations in a small number of hepatocytes and that hepatocellular carcinomas arise through stepwise evolutional changes in these cells.
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000648:ultrastructure; D002462:Cell Membrane / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic / Q000648:ultrastructure; D003599:Cytoskeleton / Q000648:ultrastructure; D004052:Diethylnitrosamine; D005260:Female; D006965:Hyperplasia; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000648:ultrastructure*; D008115:Liver Regeneration; D008297:Male; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D008870:Microtubules / Q000648:ultrastructure; D008871:Microvilli / Q000648:ultrastructure; D009367:Neoplasm Staging; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004052:Diethylnitrosamine