The development of chemically induced hepatocellular carcinoma in the rat proceeds through a series of premalignant changes that may ultimately progress to a primary malignant tumor. Using the selection technique based on diminished binding of preneoplasic hepatocytes to tissue culture plates precoated with asialofetuin, we have isolated poly(A+)RNA from early preneoplastic foci as well as preneoplastic persistent nodules and primary hepatocellular carcinoma induced by the Solt-Farber protocol in the Fischer rat. The steady-state poly(A+)RNA levels of genes traditionally associated with growth, differentiation and/or transformation were then determined to address the question of their temporal expression in the multistep nature of cancer development.
Ornithine decarboxylase-and P53-specific transcripts did not significantly change in preneoplastic foci but were increased in later-stage preneoplastic nodules and hepatocellular carcinoma. Albumin-specific transcripts were decreased in all hepatocellular carcinoma but there was no consistent coordinated increase in a- fetoprotein-specific transcripts. c-myc and raf transcripts increased at the very early preneoplastic foci stage and continued to increase throughout the neoplastic process. No L-myc or N-myc transcripts could be detected in any RNA sample. c-Ha-ras-specific transcripts were essentially unaltered in all RNA samples whereas no c-Ki-ras or N-ras transcripts could be detected throughout the neoplastic process. In addition, no dominant-acting transforming mutations in the ras gene family were detected by DNA transfection experiments using NIH/3T3 cells.
Certain cellular genes, designated protooncogenes, have been hypothesized to play an essential role in the neoplastic process, including hepatocellular carcinoma (HCC) [for review, see Refs. (1-3)]. An important feature in the development of most, if not all, human and experimental tumors is the appearance of distinctive premalignant cellular alterations that may undergo additional changes ultimately resulting in the malignant phenotype.