Significance of hepatic preneoplasia for cancer chemoprevention.
Hepatic preneoplasia represents an early stage in neoplastic development, preceding both benign and malignant neoplasia. This applies particularly to foci of altered hepatocytes (FAH), that precede the manifestation of hepatocellular adenomas and carcinomas in all species investigated. Morphological, microbiochemical and molecular biological approaches in situ have provided evidence for striking similarities in specific changes of the cellular phenotype of preneoplastic FAH emerging in experimental and human hepatocarcinogenesis, irrespective of whether this was elicited by chemicals, hormones, radiation, viruses or, in animal models, by transgenic oncogenes or Helicobacter hepaticus. Different types of FAH have been distinguished and related to three main preneoplastic hepatocellular lineages: (1) the glycogenotic-basophilic cell lineage, (2) its xenomorphic-tigroid cell variant, and (3) the amphophilic-basophilic cell lineage. The predominant glycogenotic-basophilic and tigroid cell lineages develop especially after exposure to DNA-reactive chemicals, radiation, hepadnaviridae, transgenic oncogenes and local hyperinsulinism, their phenotype indicating initiation by insulin or insulinomimetic effects of the oncogenic agents. In contrast, the amphophilic cell lineage of hepatocarcinogenesis has been observed mainly after exposure of rodents to peroxisome proliferators that are not directly DNA-reactive or to hepadnaviridae, the biochemical pattern mimicking an effect of thyroid hormone, including mitochondrial proliferation and activation of mitochondrial enzymes. Hepatic preneoplastic lesions are increasingly used as end-points in carcinogenicity testing, particularly in medium-term carcinogenesis bioassays. This has been complemented more recently by the use of FAH as indicators of chemoprevention, although possible pitfalls of this approach have to be considered carefully. Our ever-increasing knowledge on the metabolic and molecular changes that characterize preneoplastic lesions and their progression to neoplasia provides a new basis for rational approaches to chemoprevention by drugs, hormones or components of the diet.
Bannasch
P
P
Division of Cell Pathology- C0100, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Nehrbass
D
D
Kopp-Schneider
A
A
D000818:Animals; D014408:Biomarkers, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000473:pathology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology*
D014408:Biomarkers, Tumor