On the path to understanding the nature of cancer.

In this essay crucial problems of the origin of cancer and the development of malignancy are discussed. The problem of precancer and three ways leading to malignancy are considered: induction of tumor precursors, accumulation of genetic traits common for tumor growth, and the role of inflammation in tumor induction. The nature of viral oncogenes and modes of their action are described in the context of their origin as a component of the viral genome. Oncogenes of RNA-containing viruses and DNA-containing tumorigenic viruses are described together with cellular protooncogenes, which are progenitors of RNA-containing viral oncogenes. Hematological malignancies are described as an intermediate form between simple tumors induced by a single oncogene and more complicated epithelial tumors. The roles of tumor suppressor genes and the interaction of several oncogenes in the formation of carcinomas and also the role of progression in tumor evolution are discussed.

Cellular aspects of alpha-fetoprotein reexpression in tumors.

The cellular basis of AFP synthesis in normal development, liver regeneration, hepatocarcinogenesis and in tumors is discussed in the review. The attempt is made to interpret the production of AFP by germ cell and liver tumors as a consequence of their origin from the cell types producing AFP in normal conditions. Thus, AFP in germ cell tumors is explained by the development of the yolk sac visceral endoderm (YSVE) in teratocarcinomas, since YSVE is the first site of AFP synthesis in the embryo. The next site of AFP production is embryonal hepatoblast and just hepatoblastomas are the maximal producers of AFP among liver cancers. The reason for AFP resumption in hepatocellular carcinomas (HCC) is not yet clear. This problem is discussed in the light of possible role of oval cells in the HCC origin and the concept of the two states of the mature hepatocyte, associated and non-associated with AFP production. The crucial role of extracellular matrix in the control of AFP-producing state of hepatocyte is emphasized.

Inducible protein in rat hepatomas with expression alternative to alpha-fetoprotein.

The rat hepatoma cell line McA RH7777 was cloned into alpha-fetoprotein-producing (AFP+) and non-producing (AFP-) sublines. A monoclonal antibody (MAb A2/3) reacting with an antigen (Ag A2/3) present only in AFP- clones or AFP- cells in mixed clones was obtained. Ag A2/3 was absent from the liver of embryonic, fetal, newborn and adult rats, but it was present in gastric and intestinal mucosa of adult rats. Ag A2/3 was found to be a heavy metal-inducible protein: Cd2+ and Pb2+ strongly induced the expression of Ag A2/3 in vivo in the liver of adult rats, while xenobiotics and CCl4 were not active in this respect. In vitro Cd2+ and Pb2+ induced Ag A2/3 expression in several AFP+ clones, leading to a simultaneous marked decrease of AFP+ cells from such clones. The effect of Cd2+ in the induction of Ag A2/3 and suppression of AFP was reversible. SDS PAGE revealed one protein band with an m.w. close to 45,000, which was not sensitive to mercaptoethanol. Despite its inducible properties, Ag A2/3 was shown not to belong to metallothioneins, cytochrome P-450, glutathion-transferase or heat shock proteins families, well-known as being inducible cell stress proteins. Expression of Ag A2/3 could be one of the factors determining the high amplitude of AFP production by individual liver tumors. The nature of Ag A2/3 and its alternative expression with respect to AFP remain to be studied.

Phenotypic variability of cultured rat hepatoma cell population in respect to alpha-fetoprotein synthesis.

McA-RH 7777 hepatoma cells were cloned on 2 occasions a week apart (test cloning). Alpha-fetoprotein (AFP) phenotypes of primary and secondary clones from 55 primary clones were estimated. High interclonal heterogeneity of AFP expression was demonstrated. This variability exceeded by several orders of magnitude the mutation rate. We also found intraclonal differences in rates of variability. A "stabilizing" cloning was also carried out, aiming at the selection of AFP+ and AFP- stable cell lines. Stabilizing cloning included 7 cycles of cloning and selection of the most phenotypically stable clone. This stability was shown to be incomplete during the maintenance of clones in culture.