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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore peroxisome proliferator-perturbed hepatocyte growth regulation, robust in vitro models of liver are required. This has always posed a problem since isolated hepatocytes show a rapid loss of viability and differentiation status and cease to be useful after 3-4 days in culture. We now describe a model system in which rat hepatocytes are maintained as three-dimensional spheroids. The maintenance of hepatocyte viability and morphology in these cultures is considerably prolonged over that seen in monolayer culture and is comparable to that obtained by the use of collagen gels or dimethyl sulfoxide. The spheroid system is, however, free of any additives that may lead to artifact and free of excessive exogenous protein that may compromise subsequent analyses. Ultrastructural examination reveals extensive interhepatocyte junctional complexes and interdigitation of adjacent membranes together with the presence of bile cannalicular structures. Furthermore, hepatocytes maintained as spheroids retain expression of liver markers such as albumin and also retain their ability to respond to peroxisome proliferators: even after 12 days in culture, treatment with the peroxisome proliferator nafenopin causes a 4.5-fold increase in cytoplasmic volume fraction of peroxisomes. There is a concomitant induction of peroxisomal bifunctional enzyme and cytochrome P4504A, the enzyme markers associated with peroxisome proliferation. The spheroids also maintain expression of the peroxisome proliferator-activated receptor and preliminary data indicate that they are able to undergo replicative DNA synthesis in response to nafenopin. Hepatocyte spheroids will provide us with a model system for studying the early changes in rodent liver nongenotoxic carcinogenesis.
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PMID:Hepatocyte spheroids: prolonged hepatocyte viability for in vitro modeling of nongenotoxic carcinogenesis. 840 77

The mechanisms by which peroxisome proliferators are able to regulate metabolic processes such as fat metabolism, while at the same time creating an environment for the development of hepatocellular carcinomas, is a central issue in the non-genotoxic carcinogenesis field. The convergence of two members of the steroid receptor family (peroxisome proliferator-activated receptor, PPAR; and retinoid X receptor, RXR) has provided strong support for an oxidative stress component in this carcinogenesis process, but has yet to define clearly a pathway for the classical tumor promotion events associated with peroxisome proliferation. The findings presented here integrate a third member of the steroid receptor family into this process and suggest a novel autocrine loop and mechanism for creating both oxidative stress and tumor promotion. A central regulatory component in this pathway is farnesol which has recently been shown to induce transcription mediated by the steroid receptor family member, farnesoid X receptor (FXR). In this report, it is clearly demonstrated that farnesol can also upregulate the transcriptional events of PPAR, but most likely through a different farnesoid metabolite, resulting in the regulation of an entirely different set of genetic components. Deregulation of the activities of these receptors offers a provocative mechanism for explaining the hepatocarcinogenic effects of peroxisome proliferators in chronically treated rodents.
Carcinogenesis 1996 Feb
PMID:Convergence of three steroid receptor pathways in the mediation of nongenotoxic hepatocarcinogenesis. 862 36

Peroxisome proliferation has been associated with carcinogenesis in the liver, and estrogen intake has been associated with increased risk of cancer in the hormone target tissues. Estrogen-induced peroxisome proliferation has been observed in an estrogen target tissue, the uropygial gland in the duck. To elucidate the molecular mechanism of this process, we previously isolated the cDNA of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) from the duck uropygial gland and found that its expression was high exclusively in this tissue of duck. However, the nature of the ligand for PPARgamma1 and how estrogen might enhance PPARgamma1-regulated gene expression were not known. Here we demonstrate that estrogen treatment of animals enhanced the metabolism of arachidonic acid in the uropygial gland. Conversion of prostaglandin D2 to a metabolite was induced by estradiol treatment preceding peroxisome proliferation. High performance liquid chromatography and TLC analyses showed that the metabolite behaved chromatographically similar to prostaglandin J2 and Delta12-prostaglandin J2. Gas chromatography/mass spectrometry revealed a striking similarity of the metabolite to Delta12-prostaglandin J2, the only form among the J2 series whose natural occurrence has been detected. Furthermore, this metabolite was able to activate duck PPARgamma1 to the same extent as the same concentrations of Delta12-prostaglandin J2 and 15-deoxy-Delta12, 14-prostaglandin J2, whereas under the same conditions, prostaglandin D2 was not effective. The results suggest that estrogen treatment induced the formation of a prostaglandin D2 metabolite that activated duck PPARgamma1, causing the induction of peroxisome proliferation in the duck uropygial gland.
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PMID:Estrogen-induced production of a peroxisome proliferator-activated receptor (PPAR) ligand in a PPARgamma-expressing tissue. 980 68

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that controls the expression of a large array of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by prostaglandin J2 and fatty acid derivatives, which are its natural ligands. In addition, thiazolidinediones and nonsteroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. Several studies have recently shown that this nuclear receptor has a role expanding beyond metabolism (diabetes and obesity) with functions in cell cycle control, carcinogenesis, inflammation and atherosclerosis. This review addresses the role of PPARgamma in these processes.
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PMID:Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator. 1057 7

We have tested a new ligand for peroxisome proliferator-activated receptor-gamma, GW7845, as an inhibitor of experimental mammary carcinogenesis, using the classic rat model with nitrosomethylurea as carcinogen. Rats were first treated with a single dose of nitrosomethylurea (50 mg/kg body weight, i.p.). Starting 1 week later, they were fed GW7845, at either 60 or 30 mg/kg of diet, for 2 months. This agent significantly reduced tumor incidence, tumor number, and tumor weight at both doses. This is the first report of the use of a ligand for peroxisome proliferator-activated receptor-gamma to prevent experimental breast cancer.
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PMID:A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis. 1058 81

Conjugated linoleic acid (CLA) inhibits carcinogenesis and atherosclerotic plaque formation and delays the onset of diabetes in experimental animals. Whereas a plethora of data has demonstrated beneficial effects in rodent models, little work has been done to determine the role of dietary CLA in human health. The ability of CLA to modulate lipid metabolism appears to be a pivotal mechanism of CLA's beneficial effects in mice and rats. In particular, dietary CLA induces the expression of genes dependent in part on the transcription factor, peroxisome proliferator-activated receptor (PPAR). Furthermore, several CLA isomers are high-affinity ligands and activators for PPAR alpha. Within various rodent species and strains, dietary CLA exerts varying potencies; therefore, the differences in species' sensitivities are of great importance when trying to extrapolate the rodent data to be relevant in humans. This review presents the latest findings of the ability of CLA to alter lipid metabolism and gene expression in several different strains of mice and rats and speculates on the implications of these findings for human health.
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PMID:Species differences in the metabolism and regulation of gene expression by conjugated linoleic acid. 1062 84

In this short article, we review the conceptual basis for chemoprevention of cancer, the proven clinical efficacy of this concept, and current trends to develop new chemopreventive agents based on understanding of their mechanisms of action. Four classes of new agents, namely selective inhibitors of cyclooxygenase-2, selective estrogen receptor modulators, rexinoids (retinoids that bind selectively to the receptors known as RXRs) and ligands for the peroxisome proliferator-activated receptor-gamma are discussed in detail. The importance of developing totally new classes of chemopreventive agents is stressed, with particular emphasis on the potential usefulness of new synthetic triterpenoids derived from naturally occurring molecules.
Carcinogenesis 2000 Mar
PMID:Chemoprevention of cancer. 1068 73

Peroxisome proliferators increase hepatocyte proliferation and cause liver tumors in rodents, yet the mechanism of action is not understood. Based on studies with null mice it is known that peroxisome proliferator-activated receptor-alpha (PPARalpha) is involved. There is also evidence that Kupffer cells play a central role in peroxisome proliferator-induced carcinogenesis, most likely via mechanisms involving increases in superoxide, activation of nuclear factor kappaB and production of tumor necrosis factor-alpha (TNFalpha). However, it is not known whether PPARalpha is constitutively expressed in Kupffer cells. Therefore, the expression of PPAR isoforms in rat Kupffer and parenchymal cells was examined. Kupffer cells and hepatocytes of >99% purity were isolated from rats fed either a control diet or one containing 0.1% WY-14,643 for 1 week. Protein and RNA were obtained and PPAR expression was analyzed using northern and western blots. PPARalpha, PPARbeta and PPARgamma mRNA was detected in purified hepatocytes. In Kupffer cells, mRNA encoding PPARgamma was present while transcripts for PPARalpha and PPARbeta were not detected. Immunoblots were consistent with the results found by northern analysis. Moreover, when Kupffer cells from wild-type or PPARalpha-null mice were treated with WY-14,643 in vitro, superoxide production was similar. Combined, these results show that PPARalpha is expressed in rat parenchymal cells but not in Kupffer cells. These data are consistent with the hypothesis that parenchymal cells respond to Kupffer cell-derived TNFalpha via mechanisms dependent on PPARalpha within the parenchymal cells.
Carcinogenesis 2000 Apr
PMID:Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis. 1075 22

There is evidence from both genetic and pharmacologic studies to suggest that the cyclooxygenase-2 (COX-2) enzyme plays a causal role in the development of colorectal cancer. However, little is known about the identity or role of the eicosanoid receptor pathways activated by COX-derived prostaglandins (PG). We previously have reported that COX-2-derived prostacyclin promotes embryo implantation in the mouse uterus via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) delta. In light of the recent finding that PPARdelta is a target of beta-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPARdelta mRNA in matched normal and tumor samples revealed that expression of PPARdelta, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPARdelta is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPARdelta mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPARdelta and COX-2 mRNA in serial sections suggested they were colocalized to the same region within a tumor. Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI(2)) could serve as a ligand for PPARdelta. In addition, the stable PGI(2) analog, carbaprostacyclin, and a synthetic PPARdelta agonist induced transactivation of endogenous PPARdelta in human colon carcinoma cells. We conclude from these observations that PPARdelta, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPARdelta is transcriptionally responsive to PGI(2). However, the functional consequence of PPARdelta activation in colon carcinogenesis still needs to be determined.
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PMID:Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. 1108 69

Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3- to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-delta (PPAR-delta) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-delta in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-delta.
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PMID:Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone. 1130 99


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