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Expression of an Oncodevelopmental Gene Product (-Fetoprotein) during Fetal Development and Adult Oncogenesis¹

Department of Pathology, University of California at San Diego Medical School, La Jolla, California 92093 [S. S., H. W.]; M. D. Anderson Hospital, Houston, Texas 77030 [F. F. B.]; Cell Biology Laboratory of the Salk Institute, La Jolla, California 92037 [H. L. F., H. W.]; and Department of Biochemistry, Higashi Nippon Gakuen University, Hokkaido, Japan [H. W.]

The expression of an "oncodevelopmental" protein, ₁-fetoprotein (AFP), has been systematically studied in rats during normal development and during regeneration of the liver by fetal rat hepatocytes in vitro, in rats bearing transplantable hepatomas, in rats fed chemical carcinogens, and in mice that spontaneously develop hepatomas. AFP is a serum protein made normally during fetal and neonatal stages by liver and yolk sac cells. In newborn rats at approximately 4 weeks of age, the production of AFP is abruptly terminated, a process which is closely associated with cessation of liver cell proliferation. In adult rats, AFP production recurs following the reinitiation of hepatic DNA synthesis induced by partial hepatectomy or by the administration of hepatotoxic chemicals. Detailed metabolic and direct labeling studies of fetal rat hepatocytes in vitro also demonstrate a kinetically similar pattern of hepatocyte DNA synthesis and AFP production. In vitro studies utilizing combined autoradiography for DNA-synthesizing cells and immunofluorescence for AFP-containing cells demonstrates that replicating hepatocytes produce AFP; however, available data do not yet permit a distinction between G₁ (pre- or postmitotic) and/or G₂ production.

During growth of an AFP-producing tumor, the serum concentration of AFP may be used as an accurate index of tumor growth, and, if a transplanted tumor is removed, as a marker for metastatic growth of the tumor. Using this model, we have shown that radiation to the lung at the time of surgical removal of a growing tumor in the leg will prevent establishment and growth of pulmonary metastases and that anti-AFP serum treatment may inhibit growth of a transplantable hepatoma that produces AFP.

The exposure of rats to chemical hepatocarcinogens results in the appearance of elevated serum AFP concentrations as early as within 1 week of feeding; noncarcinogenic chemical analogs do not cause an elevation. AFP elevation also occurs with low doses of the hepatocarcinogen in the absence of detectable cell injury (by morphological examination or serum enzyme levels) or any other known morphological or biochemical change. This may represent a highly selective derepression of protein synthesis that occurs following the formation of a complex between the metabolites of the carcinogen and specific chromatin loci. Although every rat so far treated with even subcarcinogenic doses of hepatocarcinogens has elevated serum AFP concentrations, many primary carcinogen-induced hepatomas do not produce detectable AFP. Either there is a subsequent change in the preneoplastic AFP-producing cell that occurs prior to irreversible neoplastic alteration, or the hepatocytes originally influenced by the carcinogen to produce AFP are not necessarily the same cells that are the progenitors of the hepatoma produced by more prolonged exposure. The serum AFP concentrations of C3H-A^rN tB mice that spontaneously develop hepatocellular carcinomas do not demonstrate an increasing elevation of serum AFP with age but have elevated AFP's associated with the appearance of tumors. Thus, elevated AFP does not relate to the genetic predisposition to hepatoma development in this mouse strain.

Finally, AFP is not a general immunosuppressive, although some in vitro immune responses are affected by AFP.

In conclusion, the production of AFP is associated with normal hepatocyte division in both fetal and adult rats and with exposure to chemical carcinogens in the presence or absence of hepatocyte proliferation. The derepression of the expression of this oncodevelopmental protein provides a system for the study of gene expression in normal development, following the response to hepatocellular injury and during and after exposure to chemical carcinogens. A specific biological function of AFP remains unidentified.

¹ Presented at the Conference, "Regulation of Gene Expression in Development and Neoplasia," June 2 to 5, 1976, Santa Ynez, Calif. Supported by Grants CA-14312 and CA-14195 from NIH.

² Presenter. Recipient of Contract N01-CP-33403 from the National Cancer Institute. To whom requests for reprints should be addressed.

³ Recipient of Grant BM-S574-05471 from the National Science Foundation.