Inherent increase of apoptosis in liver tumors: Implications for carcinogenesis and tumor regression

Abstract

In the past few years, scientific interest has focused on We quantitatively assessed rates of cell replication and the process of apoptosis. Like cell replication, apoptosis is of apoptosis during the development and regression of controlled by the networks of positive and negative growth liver cancer. In rats, apoptotic activity gradually insignals. 3,[6][7][8][9][10][11] Currently prevailing views assume that maligcreased from normal liver to putative preneoplastic foci nant cells are incapable of apoptosis and/or are not responsive (PPF), to hepatocellular adenoma (HCA), and to hepatoto death signals, thereby allowing unrestrained growth of cellular carcinoma (HCC). At all stages, rates of cell replicancer. cation were higher than of apoptosis, allowing a prefer-We studied the role of apoptosis for carcinogenesis and ential net gain of (pre)neoplastic cells. As in rats, in tumor reversion in rat and human liver. Liver cancer is human HCC, birth and death rates were increased maniamong the eight leading causes of cancer death worldwide; fold, indicating a species-independent phenomenon. Imtherapeutic possibilities are very limited and prognosis is plications of the increasing cell turnover were studied usually poor. 12 Etiologic factors include genotoxic agents such in rats using the administration and withdrawal of naas certain mycotoxins or hepatitis B virus, and numerous fenopin (NAF), a liver mitogen and nongenotoxic carcinnongenotoxic exposures, e.g., ethanol, cytotoxic and inflamogen. Prolonged NAF treatment enhanced cell number matory events, steroid hormones, as well as overnutrition, in normal liver by 25%, while PPF and liver tumors were dietary constituents and some drugs, all of which may enamplified at least 100-fold. After stopping NAF treathance the growth rate of precancerous and cancerous lesions ment, cell replication ceased, while cell elimination by in the liver. 12,13 Experimental results on cancer prestages apoptosis was increased in normal and (pre)neoplastic (putative preneoplastic foci [PPF]) in this organ were not liver. HCA and HCC showed the most pronounced shifts consistent with the concept of failure of apoptosis during carfrom replication toward apoptosis. As a result, 5 weeks cinogenesis. Rather, PPF showed rates of apoptosis much after halting NAF, 20% of cells in normal liver, but about higher than normal liver; thus, the high rate of cell replica-85% of (pre)neoplastic lesions including HCC, were elimtion in PPF was largely counteracted and net growth was inated. The implications of these findings include that impeded. 11,14,15 Tumor promotion by liver mitogens or overnongenotoxic carcinogens can act as survival factors feeding inhibited apoptosis and enhanced survival of cells even for malignant cells. Furthermore, tumor cells not preferentially in PPF, thereby allowing their selective only exhibit excessive proliferation, but also undergo growth; conversely, withdrawal of these survival/growth facapoptosis at rates that far exceed those in normal tissue.tors enhanced apopt...

Levels of transforming growth factor β and transforming growth factor β receptors in rat liver during growth, regression by apoptosis and neoplasia

“…This procedure synchronizes DNA synthesis and, presumably, apoptosis in the liver to single peaks per day, which are approximately 12 hours apart (maximal DNA synthesis at about 8 PM). [7][8][9] The treatment of the animals followed published protocols. 5,31 Briefly, cyproterone acetate (CPA, Schering AG, Berlin, FRG) and nafenopin (NAF, Ciba-Geigy, Basel, Switzerland) were given once per day at 8 AM by gavage.…”

“…2,[5][6] Apoptosis also occurs in preneoplastic and neoplastic lesions in all stages of hepatocarcinogenesis. 2,[6][7][8][9] Tumor promoters inhibit apoptosis, thereby accelerating the growth of preneoplastic cell populations and the development of frank neoplasia. 2,6,7,9 Thus far, endogenous mediators (cytokines) which are involved in the control of these effects and their mode of action are insufficiently known.…”

Retinoic acid treatment induces apoptosis or expression of a more differentiated phenotype on different fractions of cultured fetal rat hepatocytes

“…This finding is not surprising, given the quiescent state of this organ, in which there is no significant cell turnover. However, apoptosis may be induced in vivo in particular conditions, such as starvation, 23 liver regeneration after partial hepatectomy, 24 Pb nitrate administration, 25,26 during hepatocarcinogenesis, 27,28 or in vitro after transforming growth factor ␤ 1 treatment, 29 treatment with tumor necrosis factor ␣ following the addition of actinomycin D, 30 the use of microtubule-depolymerizing drugs, 31 or protein kinase C inhibitors. 32 Apoptotic events have never been described during liver morphogenesis, in contrast to other organs.…”

Inherent growth advantage of (pre)malignant hepatocytes associated with nuclear translocation of pro-transforming growth factor α

“…Rodent liver provides excellent tools for functional studies on hepatocarcinogenesis (Pitot, 1990;Grasl-Kraupp et al, 1997;Grisham, 1997). Treatment of rats with genotoxic carcinogens, such as N-nitrosomorpholine (NNM), induces single initiated hepatocytes that are detectable by their selective immunoreactivity for placental glutathione-S-transferase (GSTp þ cells); a considerable fraction of these cells develops to GSTp þ (pre)malignancy (Grasl-Kraupp et al, 2000).…”

“…Although human HCC often do not express GSTp due to epigenetic silencing of the gene, GSTp þ lesions of rats and (pre)malignant lesions in human liver show significant similarities, such as mutations of the wnt-pathway, overexpression of TGFa, IGF-I and -II and other growth factors (Miller et al, 1995;Grisham, 1997;Yamada et al, 1999;Yang et al, 2003). Rates of replication and death of GSTp þ cells, and thus overall cell turnover, are somewhat reduced in the single-cell stage, but are significantly increased from the two-cell stage onwards (Grasl-Kraupp et al, 1997. Thus, initiation causes a change in the growth-regulatory network that becomes evident after the first replication cylce of GSTp þ cells.…”