Molecular pathology of early stage chemically induced hepatocarcinogenesis

In the early stage of chemically induced hepatocarcinogenesis, rare hepatocytes are transformed into preneoplastic hepatocytes, which progressively evolve into cells with increasing neoplastic phenotypes. Preneoplastic hepatocytes have gene expression different from normal hepatocytes, presumably from the outset. Some of these gene products are related to the growth and survival of the preneoplastic hepatocytes themselves, while others seem to involve the interaction of preneoplastic hepatocytes with non‐parenchymal cell components (paracrine mechanism). Carcinogen treatment, in contrast, usually causes chronic liver injury and continuous liver regeneration, which causes selective expansion of neoplastic hepatocytes due to the fact that the neoplastic hepatocytes are resistant to cellular stress, while proliferation of normal hepatocytes is suppressed by this stress. The formation of neoplastic lesions seems to create a new microenvironment within/around the lesions, which in turn may isolate the preneoplastic hepatocytes from the normal hepatic tissues, further favoring the survival and proliferation of the preneoplastic hepatocytes. Transformation of normal hepatocytes into preneoplastic hepatocytes, their selection for growth and their isolation from the normal hepatic environment are therefore considered the fundamental principles for hepatocarcinogenesis, and this unique gene expression in preneoplastic hepatocytes together with changes in the affected liver are thought to be related to these phenomena.