Expression of protein markers in malignant hepatoma. Evidence for genetic and epigenetic mechanisms

Abstract

Using light microscopic, ultrastructural, histochemical, and immunocytochemical tissue methods, a comparative study was done on distinctive alpha‐1‐antitrypsin containing tumor tissue inclusions in hepatoma, and alpha‐1‐antitrypsin globules in non‐neoplatic liver cells in inherited alpha‐1‐antitrypsin deficiency. These findings were compared with serum alpha‐1‐antitrypsin phenotypc. The parallel emergence of alpha‐1‐antitrypsin, alpha‐2‐macroglobulin, and alpha‐fetoprotein as tumor tissue markers in hepatoma was demonstrated in association with normal serum alpha‐1‐antitrypsin phenotype. In contrast, alpha‐1‐antitrypsin deficiency liver globules were reactive only for alpha‐1‐antitrypsin and exclusively associated with alpha‐1‐antitrypsin phenotypic variation. These features and other morphologic differences characteristic of the hepatoma inclusions (larger size, greater shape variability, more frequent extracellular location, presence in neoplastic tissue alone, and ultrastructural heterogeneity) support the conclusion that two separate mechanisms of alpha‐1‐antitrypsin deposition are involved in malignant hepatoma. The first mechanism is genetically determined, related to the presence of the alpha‐1‐antitrypsin Z allele. The second mechanism is non‐genetic in nature, confined to tumor tissue, and probably represents primary protein synthesis by tumor cells. Embryonic correlates in site of synthesis and presence in serum are known for alpha‐1‐antitrypsin, alpha‐2‐macroglobulin, and alpha‐fetoprotein. Due to the disappearance of alpha‐fetoprotein, however, this parallelism is not found in the normal adult. Therefore, the emergence of these marker proteins together in hepatoma raises the possibility that they represent fetal gene products arising from an epigenetic (oncodevelopmental) mechanism. Copyright © 1980 American Cancer Society