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PubMed1990

Transforming growth factor beta 1 in liver carcinogenesis: messenger RNA expression and growth effects.

Transforming growth factor beta 1 (TGF-beta 1) is a potent inhibitor of hepatocyte proliferation. Since loss of sensitivity to growth inhibition is thought to contribute to the development of neoplasia, we analyzed the expression of TGF-beta 1 mRNA during hepatocarcinogenesis in vivo and in cultured liver epithelial cells (oval cells) obtained from carcinogen-treated animals. We found that TGF-beta 1 mRNA increases in the liver during carcinogenesis and that, at the early stages of the process, oval cells but not hepatocytes contain the growth factor mRNA. Moreover, immortalized, nontumorigenic oval cells (LE/6 cell line) continued to produce TGF-beta 1 mRNA in culture. TGF-beta 1 message markedly decreased upon cell transformation, but message levels, although generally low, were variable in various tumor cell clones. A consistent feature of the tumorigenic cell lines was a loss of sensitivity to TGF-beta 1 growth inhibition. Tumor cells could bind TGF-beta 1 with similar capacity as normal cells and had the same type of receptors (Mr 280,000, 85,000, and 65,000) capable of binding iodinated TGF-beta 1, suggesting that the loss of sensitivity to TGF-beta 1 in transformed liver epithelial cells involves postreceptor mechanisms. Further studies showed that c-myc is not a target for TGF-beta 1 in liver epithelial cells and that TGF-beta 1 no longer induces fibronectin mRNA in transformed cells. The data presented are consistent with the hypothesis that TGF-beta 1 secreted during liver carcinogenesis may inhibit the proliferation of normal cells while providing a selective advantage for the growth of cells that are "partially transformed" and are unresponsive to the factor.

Animals↗
PubMed1990

Persistent reduction of indigenous DNA modification (I-compound) levels in liver DNA from male Fischer rats fed choline-devoid diet and in DNA of resulting neoplasms.

Reduced levels of putative indigenous DNA modifications (I-compounds) in liver DNA of male Fischer 344 rats fed a hepatocarcinogenic choline-devoid (CD) diet for up to 7 mo have been previously reported. To investigate the persistence of this effect and possible relationships between I-compounds and hepatocarcinogenesis, liver DNA modifications of tumor-free male rats fed a CD diet for 3, 6, 9, or 12 mo, followed by a choline-supplemented (CS) diet to 16 mo, were compared with those in rats fed exclusively the CD or CS diet for 16 mo by a 32P-postlabeling assay. In addition, DNA from nontumorous and tumorous tissues of rats fed the CD diet similarly for 12 or 16 mo was analyzed. It was found that total I-compound levels in male rats consecutively fed CD and CS diets for various lengths of time were similar to those in rats fed the CD diet only and significantly lower than those in rats fed the CS diet only. I-compound levels of nontumorous regions from tumor-bearing livers were 73% of those in tumor-free livers from the same treatment group. I-compound levels were further reduced, some to undetectable levels, in tumor tissues and exhibited an inverse relationship with tumor incidence. The patterns and levels of I-compounds in liver DNA of CD diet-fed female rats, which were not susceptible to CD diet-induced hepatocarcinogenesis, on the other hand, were not significantly different from those of controls. Thus, reduction of I-compound levels by feeding a CD diet lasted for many months after changing from the CD to the CS diet. Whether this persistent DNA alteration contributes to carcinogenesis remains to be determined.

Animals↗
PubMed1990

No enhancement by phenobarbital of the hepatocarcinogenicity of a choline-devoid diet in the rat.

An experiment was performed to test whether inclusion of phenobarbital in a choline-devoid diet would increase the hepatocarcinogenicity of the diet. Groups of 5-week old male Fischer-344 rats were fed for 7-25 months semipurified choline-devoid or choline-supplemented diets, containing or not 0.06% phenobarbital. No hepatic preneoplastic nodules or hepatocellular carcinomas developed in rats fed the plain choline-supplemented diet, while one preneoplastic nodule and one hepatocellular carcinoma developed in two rats fed the same diet containing phenobarbital. The incidence of preneoplastic nodules and of hepatocellular carcinomas was 10% and 37%, respectively, in rats fed the plain choline-devoid diet, and 17% and 30%, in rats fed the phenobarbital-containing choline-devoid diet. The results evinced no enhancement of the hepatocarcinogenicity of the choline-devoid diet by phenobarbital. Sporadic neoplastic lesions were observed in organs other than the liver of some of the animals, irrespective of the diet fed.

Animals↗
PubMed1987

Growth in culture and tumorigenicity after transfection with the ras oncogene of liver epithelial cells from carcinogen-treated rats.

Two epithelial cell lines designated LE/2 and LE/6 were established from cells isolated by centrifugal elutriation from the livers of carcinogen-treated rats. Both cell lines exhibit some characteristics of fetal liver cells, such as the expression of the 2.3-kilobase alpha-fetoprotein mRNA, aldolase A, and lactate dehydrogenases 4 and 5. Primary cultures contain gamma-glutamyl transferase-positive cells which do not proliferate in vitro. After the first passage, the LE/2 and LE/6 cell lines are uniformly gamma-glutamyl transferase negative. Neither cell line is transformed as assayed by morphology, anchorage-independent growth, or tumor formation in nude mice. By the 50th passage, LE/6 cells form numerous colonies in soft agar in the presence of epidermal growth factor, while no colonies grow in medium lacking this growth factor. Clonal cell populations derived from five epidermal growth factor-induced soft agar colonies were not tumorigenic in nude mice. This indicates that, although epidermal growth factor-responsive late passage cells had acquired some of the phenotypic properties commonly associated with tumor cells, these cells were not fully transformed. Transformation of LE/6 cells was accomplished by transfection of the rasH oncogene (EJ). Subcutaneous inoculation of rasH (EJ)-transfected LE/6 cells produced tumors at the site of injection with histological features of moderate to well-differentiated trabecular hepatocellular carcinomas. Tumor cell lines derived from the nude mouse tumors are gamma-glutamyl transferase positive and express alpha-fetoprotein mRNA. One clonal cell line expresses both alpha-fetoprotein and albumin mRNA. These results show that nonparenchymal liver epithelial cells transfected with an activated oncogene can give rise to differentiated hepatocellular tumors similar to those induced in livers of rats fed a carcinogenic diet.

Animals↗
PubMedDate not supplied

Choline: an essential dietary nutrient?

Choline (trimethyl-beta-hydroxyethylammonium) is a quaternary amine which is widely distributed in plants and animals. It contains three methyl groups which are important in a number of metabolic reactions, including the synthesis of methionine and carnitine. Choline is also a component of the phospholipids phosphatidylcholine and sphingomyelin, important constituents of all cell membranes. Finally, choline is necessary for the synthesis of the neurotransmitter acetylcholine. Although this compound is considered an essential nutrient in numerous mammalian species, this has not been established for humans.

Animal Nutritional Physiological Phenomena↗
PubMed1978

Enhancement of DL-ethionine-induced liver carcinogenesis in rats fed a choline-devoid diet.

The effects of a choline-devoid (CD) or a choline-supplemented (CS) diet on the induction of liver tumors in rats by DL-ethionine were investigated. Groups of male outbred Sprague-Dawley rats were fed a plain CD or a plain CS diet, or the same diets containing 0.05% DL-ethionine. Hepatocellular carcinomas developed in 50% of the rats fed the CD+ethionine diet for 14 weeks and in about 80% of the rats fed the same diet for 22-30 weeks. No hepatocellular carcinomas developed in rats fed the CS+ethionine diet, the plain CD diet, or the plain CS diet up to 30 weeks. The findings suggest that a CD diet alters the response of rat liver to DL-ethionine and leads to an early and enhanced induction of hepatocellular carcinoma.

Animals↗
PubMed1985

Hepatocarcinogenic and promoting action of a choline-devoid diet in the rat.

Male Fisher 344 rats were solely fed a choline-supplemented diet for 65 to 105 weeks or a choline-devoid diet for 24 to 102 weeks. Hepatocellular carcinomas developed in the latter animals, beginning at 24 weeks. Other groups of rats were given a single dose of 20 mg diethylnitrosamine/kg, 18 h after a partial hepatectomy and were fed, 4 weeks thereafter, either a choline-supplemented, or a choline-devoid diet for up to 48 weeks. In rats fed the choline-supplemented diet, the only relevant lesion observed was a small transect number of foci of enzyme-altered hepatocytes. On the other hand, a significant number of foci, of preneoplastic nodules, and of hepatocellular tumors developed in rats fed the choline-devoid diet. The results obtained are consistent with those previously reported by others, indicating that diets devoid of choline, or of choline and methionine, are carcinogenic. The diets appear to act as complete carcinogens, since they are also efficient promoters of chemical hepatocarcinogenesis, as shown again, in the present study, by the results obtained in the diethylnitrosamine-pretreated rats.

Animals↗
PubMed1986

Liver tumour promotion by chemicals: models and mechanisms.

Tumour promotion is defined as the process whereby a carcinogen initiated organ develops focal proliferations such as nodules, polyps or papillomas, one or more of which become precursors for subsequent steps in the carcinogenic process. The available models for a sequential analysis of carcinogenesis in liver have been examined within the framework of this operational definition with respect to the models themselves as well as the promoted hepatocytes. Using initiation-promotion protocols, several promoters which differ in the biological responses they elicit have been identified. The key issue in promotion pertains to the mechanisms involved in the focal proliferation of the initiated hepatocytes. The resistant hepatocyte model and perhaps the phenobarbital model suggest that focal proliferation of the initiated hepatocyte is induced by exerting a selective mitoinhibitory effect on the surrounding cells while permitting the initiated hepatocyte to respond to the proliferative stimulus, whether it is exogenous or endogenous. The promoter orotic acid, on the other hand, is a natural precursor of pyrimidine nucleotide biosynthesis and is neither an inducer nor an inhibitor of liver cell proliferation but it creates an imbalance in cellular nucleotide pools. Since nucleotides are intermediates in DNA synthesis as well as in the glycosylation of proteins and lipids including that of membranes, it has been postulated that the promotional effect of orotic acid is mediated through this imbalance affecting both DNA and membranes. There is some experimental evidence for this. The importance of this hypothesis is that it raises the possibility of achieving promotion in several organs by disturbing the normal nucleotide pool patterns. Indeed orotic acid has also been found to promote duodenal cancer. The finding that hepatic nodules, regardless of how they have been promoted, exhibit a common biochemical pattern with resistance to several agents has raised some important issues. For example, what is the basis for the resistant phenotype and how is it related to cancer development? Are all initiated hepatocytes identical? If not, do all promoters exert their effect on the same population of initiated hepatocytes? Is the heterogeneity of the initiated hepatocyte population generated by the carcinogen due to the induction of more than one critical lesion: a primary lesion responsible for initiation and secondary lesions in which different types of initiated cells are selected by different promoters?(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed1987

Probable free radical effects on rat liver nuclei during early hepatocarcinogenesis with a choline-devoid low methionine diet.

Fischer-344 rats fed a choline-devoid diet show lipid peroxidation in the liver nuclei, beginning at 1 day, reaching a peak at 3 days, and subsequently declining by 35 days. Lipid peroxidation in the mitochondria was seen first at 3 days, increased to a maximum at 28 days, and decreased after 35 days to undetectable values at 49 days. Lipid peroxidation was found in both nuclear and mitochondrial fractions both before and after stripping of their outer membranes. No microsomal lipid peroxidation could be detected at any time up to 63 days. The animals fed the same diet supplemented with choline showed no lipid peroxidation in any liver fraction. Animals given CCl4 showed the expected lipid peroxidation in the microsomes but not in the nuclear fraction. The administration of the free radical trapping agent, N-tert-butyl-alpha-phenylnitrone, prevented completely or almost so, microsomal lipid peroxidation induced by CCl4 and nuclear lipid peroxidation in the animals fed the choline-devoid, low methionine diet. The genesis of free radicals in the livers of rats fed a choline-devoid diet is considered as a likely hypothesis for the observed lipid peroxidation. The lipid peroxidation in turn is considered to be closely related to the induction of liver cell death and to the production of alterations in DNA. The DNA alterations coupled with regenerative liver cell proliferation suggest an attractive hypothesis for the initiation of hepatocarcinogenesis in rats fed a choline-devoid diet.

Aldehydes↗