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Experimental Hepatocellular Carcinogenesis¹

Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

The sequential development of lesions in the liver leading to hepatocellular carcinoma in experimental animals appears to follow a similar pattern irrespective of the carcinogen. The speed with which the lesions develop is related to the chemical, the dose and dosing schedule, and the diet fed. In studies with aflatoxin B₁ there is a predictable series of morphological expressions beginning with focal areas of hydropic degeneration (Stage 1); hyperplastic basophilic cells, singly or in close association with Stage 1 (Stage 2); nodular hyperplasia of parenchymal cells which become progressively more abnormal (Stage 3); transitional cell changes (Stage 4); and, ultimately, hepatocellular carcinoma (Stage 5).

In our judgment, Stages 1, 2, and 3 may be necessary but not sufficient alterations to result in cancer. Cells in Stages 2 and 3 may have undergone reversible transformations and may never progress to malignancy. The cells in Stages 1 and 2 exhibit early a loss of several enzymes identified histochemically, but the extent of the loss appears to vary according to the time in development at which the lesion is sampled. Labeling with [³H]thymidine indicates an early burst of DNA synthesis in the small basophilic foci, followed by expansion of the area with labeling of cells at the periphery and few if any in the center. Later, in Stage 3, cells at the center of the lesion again label, and, in Stage 4, labeled cells and mitoses are abundant. Stage 3 may or may not be reversible, but not all such lesions progress to carcinoma. Stage 4 probably is irreversible; the cells and architecture are markedly abnormal and may be considered premalignant. Correlation of the marker enzyme deficiency, cell turnover indices, biochemical alterations, and morphological changes can aid in elucidation of cellular evolution culminating in neoplasia. Manipulation of dietary treatment offers a powerful tool in these studies.

¹ Presented at the Conference "Early Lesions and the Development of Epithelial Cancer," October 21 to 23, 1975, Bethesda, Md.