Basic Science of Liver Cancer Stem Cells and Hepatocarcinogenesis

Abstract

Environmental agents, including carcinogens, diet and genetic predisposition, are associated with toxicity-induced liver cell death and chronic inflammation. Both liver cell death and inflammation can contribute to development of compensatory hepatocyte proliferation and to hepatocarcinogenesis

High-affinity low-capacity and low-affinity high-capacity N-acetyl-2-aminofluorene (AAF) macromolecular binding sites are revealed during the growth cycle of adult rat hepatocytes in primary culture

“…Scatchard analyses provide further evidence of the growth cycle dependence of the levels of Site I and Site II constants. Taken together, the results have important implications for mechanisms of chemical hepatocarcinogenesis, even if non-parenchymal or liver stem cells are adduct-forming bystanders and/or carcinogen targets (Koch and Leffert, 2015).…”

“…A critical question remains: As hepatocytes proliferate in vitro, can one or more type of precursor cell (Koch and Leffert, 2015), associated with altered Site I and/or Site II expression, emerge from AAF treatment to give rise to HCC? Continued investigations with this AAF processing and adduct-forming system may provide an answer to this most significant question, particularly if the longevity of this system 3 can be extended to time intervals required for AAF to induce HCC in vivo (Teebor and Becker, 1971).…”

N-acetyl-2-aminofluorene (AAF) processing in adult rat hepatocytes in primary culture occurs by high-affinity low-velocity and low-affinity high-velocity AAF metabolite-forming systems

“…One plausible explanation for the two principal AAF metabolizing systems is that alternatively spliced Cyp1A2 isozymes, like the single-copy human gene (Schweikl et al, 1993;Allorge et al, 2003;Zhou et al, 2010;GeneCards Human Gene Database, 2017), operate in adult rat hepatocytes: one in the nucleus (System I [with one set of Km and VMAX values]); and, the other in the cytoplasm (System II [with another set of Km and VMAX values]). Although neither AAF metabolism via non-parenchymal cells (≤ 5% of the total population) nor bystander effects (Koch and Leffert, 2015) were rigorously excluded, autoradiography with [ 3 H]-AAF demonstrated dissimilar distributions of covalently bound intracellular macromolecular adducts (cytoplasm >> nucleus), supporting N-OH-AAF generating Cyp1A2 metabolic activity at both hepatocellular sites.…”

“…Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide (> 600,000 deaths per year) and the seventh most common cancer (American Cancer Society, 2017;Koch and Leffert, 2015;Mishra et al, 2009;Yang and Roberts, 2010). A wealth of information about the phenomenon of chemical hepatocarcinogenesis has come from investigations of the induction of adult rat HCC (Becker, 1975;Miller, 1975;Weinstein, 1978).…”

“…While much is known about the metabolic pathways of AAF, little is known about the cell biology and pharmacology of AAF processing inside living hepatocytes, the major intrahepatic cellular target of this procarcinogen (Koch and Leffert, 2015). A series of experiments were conducted using a well-characterized primary adult rat hepatocyte culture system to quantify the early biochemical processing and biological effects of AAF, and to elucidate the intracellular properties of processing in relation to hepatocyte DNA synthesis and cell division.…”