UMLS:C0596263 - FACTA Search

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

There is growing evidence to show that hepatic oval cells contribute to liver regeneration, dysplastic nodule formation, and hepato-carcinogenesis. Peroxisome proliferator-activated receptors (PPARs) and their ligands play an important role in cell growth, inflammatory responses, and liver pathogenesis including fibrosis and cancer. However, little is known about the role of PPARgamma/its ligands in the growth and differentiation of hepatic oval cells. In this study, we found that OC15-5, a rat hepatic oval cell line, expressed PPARgamma at mRNA and protein levels, and a natural ligand for PPARgamma, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), and a synthetic ligand, ciglitazone, inhibited growth of OC15-5 cells by arresting at G1-S in a dose-dependent manner. Apoptosis was also induced in OC15-5 cells by 15d-PGJ2 treatment. In OC15-5 cells treated with 15d-PGJ2, the expression of CDK inhibitor, p27(Kip1), was up-regulated, while that of p21(WAF1/Cip1), p18(INK4C) CDK2, CDK4, and cyclin E was unchanged. In addition, delayed up-regulation of AFP expression was observed in OC15-5 cells after 15d-PGJ2 or ciglitazone treatment. This is the first report to show that the PPARgamma ligand was involved in the growth, cell cycle, and differentiation of hepatic oval cells, raising the possibility that the PPARgamma ligands may regulate liver regeneration and hepato-carcinogenesis.
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PMID:Peroxisome proliferator-activated receptor gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2, and ciglitazone, induce growth inhibition and cell cycle arrest in hepatic oval cells. 1532 52

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been found to induce cell death in a variety of cells. In this regard, we reported recently that 15-deoxy-Delta-(12,14)-prostaglandin J2 (15dPG-J2), a specific ligand of the nuclear receptor PPARgamma, inhibits proliferation and induces cellular differentiation and apoptosis in the breast cancer cell line MCF-7. In addition to PPARgamma activation other proteins, such as NF-kappaB and AP1, have been shown to be targets of 15dPG-J2. However, the mechanism by which 15dPG-J2 triggers cell death is still elusive. Our results demonstrate that 15dPG-J2 initiates breast cancer cell death via a very rapid and severe impairment of mitochondrial function, as revealed by a drop in mitochondrial membrane potential (DeltaPsi(m)), generation of reactive oxygen species (ROS) and a decrease in oxygen consumption. In addition, 15dPG-J2 can also activate an intrinsic apoptotic pathway involving phosphatidyl serine externalization, caspase activation and cytochrome c release. Bcl-2 over-expression and zVADfmk, albeit preventing caspase activation, have no effect on 15dPG-J2-mediated mytochondrial dysfunction and loss of cell viability. In contrast, the addition of radical scavengers or rotenone, which prevent 15dPG-J2-induced ROS production, block the loss of cell viability induced by this prostaglandin. Finally, 15dPG-J2-induced cell death appears to involve disruption of the microtubule cytoskeletal network. Together, these results suggest that PG-J2-induced mitochondrial dysfunction and ROS production inevitably leads to death, with or without caspases.
Carcinogenesis 2005 Jan
PMID:15-deoxy-Delta-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism. 1548 93

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor involved in various processes including the inflammation and carcinogenesis. The aim of the present study was 1) to examine the mRNA and protein expression of PPARgamma in gastric cancer (GC); 2) to evaluate the effect of PPARgamma ligand (ciglitazone) on the proliferation and apoptosis of GC cell line; and 3) to assess the levels of gastric tissue proinflammatory cytokines, IL-1beta and IL-8, and plasma gastrin in GC patients before and after Helicobacter pylori (H. pylori) eradication. The trial material included 30 H. pylori-negative controls and 30 sex- and age-matched GC patients without or with H. pylori before and after its eradication. Expression of tissue PPARgamma, tissue levels of IL-1beta and IL-8, and plasma concentration of gastrin were significantly higher in H. pylori-positive GC compared to controls, but H. pylori eradication significantly reduced these parameters. Kato III cells incubated with alive H. pylori upregulated PPARgamma expression and ciglitazone inhibited cell proliferation and induced apoptosis. PPARgamma, proinflammatory cytokines and plasma gastrin appear to be implicated in H. pylori-related gastric carcinogenesis and PPARgamma agonists may have potential in cancer therapy.
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PMID:Implication of peroxisome proliferator-activated receptor gamma and proinflammatory cytokines in gastric carcinogenesis: link to Helicobacter pylori-infection. 1549 68

Associations between polymorphisms in genes (SNPs) involved in the arachidonic acid (AA) pathway and colorectal adenomas have been investigated in a Dutch case control study including 384 cases and 403 polyp-free controls. Twenty-one polymorphisms in seven candidate genes were studied and a potential modifying effect of fish consumption was considered. A protective effect on colorectal adenomas was found for the CT genotype of SNP H477H in PPARgamma and the GC genotype of SNP V102V in COX-2 (OR 0.63, 95% CI 0.45-0.89 and OR 0.65, 95% CI 0.46-0.92, respectively) compared with the homozygous major genotypes. An increase in adenoma risk was observed for the TC genotype of SNP c.2242T-->C in COX-2 (OR 1.47, 95% CI 1.07-2.00) compared with the TT genotype. Analysis with estimated haplotypes confirmed these associations and revealed three additional associations with COX-2, sPLA(2) and 15LOX haplotypes. Fish consumption modified the associations with COX-2 and PPARdelta genotypes. For SNP c.-789C-->T in PPARdelta the major genotype showed a decrease in adenoma risk for those in the highest tertile of fish consumption (T3), as compared with the lowest tertile (T1) (OR 0.65, 95% CI 0.41-1.02). Protective effects were also observed for SNPs V102V and c.2242T-->C in COX-2 and high fish intake. The interaction between fish consumption and c.2242T-->C was statistically significant, with an OR for the TT genotype and high fish consumption of 0.52 (95% CI 0.27-1.01) as compared with low fish intake. These results indicate that SNPs in genes involved in the AA pathway are associated with colorectal adenoma risk. Some of these associations are modified by fish consumption.
Carcinogenesis 2005 Feb
PMID:Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption. 1555 Apr 53

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily initially shown to be a key regulator of fat cell differentiation, can inhibit cell growth and induce apoptosis in colon cell lines. There are heterozygous loss of function mutations in the gene encoding PPARgamma in tumors from approximately 10% of human colon cancer patients. A common structural polymorphism has been detected in the PPARgamma gene at codon 12 (Pro12Ala). We investigated the hypothesis that the PPARgamma Pro12Ala polymorphism is associated with colorectal adenoma risk in a recently concluded case-control study of incident sporadic colorectal adenomas (163 cases and 212 controls). The multivariate-adjusted odds ratio (OR) for incident sporadic colorectal adenoma was 0.65 (95% CI 0.39-1.09) for those with the Pro12Ala or Ala12Ala genotype compared with those with the Pro12Pro genotype. Multivariate-adjusted inverse associations with the Ala12 variant were more pronounced among those who were female (OR 0.36, 95% CI 0.18-0.75) or did not take non-steroidal anti-inflammatory drugs (OR 0.38, 95% CI 0.14-1.00). Marginally significant results were observed among those with a lower waist:hip ratio (OR 0.52, 95% CI 0.24-1.12) or a lower body mass index (OR 0.46, 95% 0.20-1.05). Smoking was a very strong risk factor (OR 2.34, 95%CI 1.37-4.02) for colorectal adenoma among those with the wild-type (Pro12Ala) genotype, but not those with the Ala12 variant (OR 0.86, 95%CI 0.35-2.09). Larger studies are needed to validate these results, which suggest that the PPARgamma Pro12Ala polymorphism may interact with other factors to protect against colorectal adenoma.
Carcinogenesis 2005 Mar
PMID:The PPAR{gamma} Pro12Ala polymorphism and risk for incident sporadic colorectal adenomas. 1556 89

The role of peroxisome-proliferator activated receptor (PPAR)gamma in tumor growth inhibition has been extensively studied during last seven years but still remains debated. Many in vitro and xenograft studies have demonstrated that PPARgamma ligands are anti-tumorigenic due to anti-proliferative, pro-differentiation and anti-angiogenic effects. In animal models, PPARgamma ligands have shown preventive effects against chemical carcinogenesis. On the other hand, evidences are accumulating against the possible use of this ligand activated nuclear receptor in molecular targeting for cancer therapy. The growth inhibitory effects of certain PPARgamma ligands have recently been shown to be independent of PPARgamma-activation. Studies have also come up with results indicating the growth promoting effects of PPARgamma-activation, particularly in certain animal models genetically predisposed to cancer development. Loss-of-function mutations of PPARgamma in tumors and increased susceptibility of PPARgamma heterozygote knockout mice to carcinogenesis suggested a tumor-suppressing role of PPARgamma. However, recent findings do not support PPARgamma as a tumor suppressor gene. Although initial clinical trials with PPARgamma ligand troglitazone reported promising results in liposarcoma and prostate cancers, recent studies failed to show the expected therapeutic values in advanced colorectal and breast cancers. In this review, we have addressed these controversies on potential use of PPARgamma ligands in cancer therapy.
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PMID:Can PPAR gamma ligands be used in cancer therapy? 1557 13

Troglitazone is one of the thiazolidinedione (TZD) class of anti-diabetic drugs and a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma). Troglitazone and other PPARgamma ligands have been shown to inhibit cell proliferation and induce cell cycle arrest in a variety of cancer cells, and have been considered as potential tumor preventive and tumor therapeutic agents. Little is known, however, about how normal or initiated cells respond to these agents during mouse skin carcinogenesis. We report here that troglitazone and another TZD, ciglitazone, dramatically inhibited mitogen-induced cellular proliferation in normal mouse skin primary keratinocytes and in the C50 keratinocyte cell line. This was accompanied by induction of cell cycle G1 phase arrest and suppression of cyclin D1, cdk4, and cdk2 expression. Troglitazone suppressed cyclin D1 expression at multiple levels. In addition, we demonstrated that PPARgamma was not expressed at functional levels in cultured mouse skin keratinocytes, and that the inhibitory effects of troglitazone on cellular proliferation and cyclin D1 expression in these cells were PPARgamma-independent. Given the important role of keratinocyte proliferation in skin carcinogenesis, our data suggest that TZD may be useful tumor preventive agents in skin.
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PMID:Troglitazone inhibits cyclin D1 expression and cell cycling independently of PPARgamma in normal mouse skin keratinocytes. 1561 May 22

Recent molecular studies have provided new insights into thyroid carcinogenesis. In thyroid papillary carcinomas at least three initiating events may occur, which are point mutations in the BRAF and RAS genes and RET/PTC rearrangements. Tumors harboring mutant BRAF and RAS are prone to progression to poorly differentiated and anaplastic carcinoma, but most likely require additional mutations to trigger this process. In thyroid follicular carcinomas, two known initiating events are RAS mutations and PAX8-PPARgamma rearrangements, and RAS predisposes to dedifferentiation of follicular carcinomas. p53 and beta-catenin mutations, found with increasing incidence in poorly differentiated and anaplastic carcinomas but not in well-differentiated tumors, may serve as a direct molecular trigger of tumor dedifferentiation. Additional evidence for progression from a preexisting well-differentiated carcinoma to poorly differentiated and anaplastic carcinoma comes from the studies of loss of heterozygosity and comparative genomic hybridization. Molecular studies, although limited by the lack of uniform histologic criteria for poorly differentiated carcinomas, revealed no genetic mutations or chromosomal abnormalities that are unique for poorly differentiated carcinoma and not present in well-differentiated or anaplastic carcinomas. This suggests that poorly differentiated carcinoma, as a group, represents a distinct step in the evolution from well-differentiated to anaplastic thyroid carcinoma, rather than an entirely separate type of thyroid malignancy.
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PMID:Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas. 1568 56

Epidemiological studies have provided evidence that high intake of saturated fat and/or animal fat increases the risk of prostate cancer, but on the other hand, diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), present in fish oils were found to reduce the risk. There are indications of an increased expression of immunoreactive PPARgamma in prostatic intraepithelial neoplasia (PIN) and prostate cancer, suggesting that PPARgamma ligands may exert their own potent anti-proliferative effect against prostate cancer. The experimental evidence for the role of cyclooxygenase-2 (COX-2) in prostate carcinogenesis is well established through several investigations. It clearly suggests the need for development of strategies to inhibit COX-2 mediated prostate carcinogenesis. However, administration of high doses of COX-2 inhibitors, such as celecoxib, over longer periods may not be devoid of side effects. We assessed the efficacy of DHA and celecoxib individually and in combination at low doses in three prostate cancer cell lines (LNCaP, DU145 and PC-3) measuring cell growth inhibition and apoptosis, and on the levels of expression of COX-2, nuclear factor-kappaB (NF-kappaBp65), and nuclear receptors, such as PPARgamma and retinoid X receptors (RXR), all of which presumably participate in prostate carcinogenesis. A 48-h incubation of prostate cancer cells with 5 microM each of DHA or celecoxib induced cell growth inhibition and apoptosis, and altered the expression of the above molecular parameters. Interestingly, the modulation of these cellular and molecular parameters was more pronounced in cells treated with low doses of DHA and celecoxib (2.5 microM each) in combination than in cells treated with the higher doses of individual agents. In conclusion, the present study demonstrates for the first time that a combination of lower doses of the n-3 PUFA, and DHA with the selective COX-2 inhibitor celecoxib effectively modulates the above cellular and molecular parameters that are relevant to prostate cancer. This raises the intriguing prospect that the use of low doses of a COX-2 inhibitor in combination with an n-3 PUFA could be a highly promising strategy for prostate cancer chemoprevention while minimizing undesired side effects.
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PMID:A combination of docosahexaenoic acid and celecoxib prevents prostate cancer cell growth in vitro and is associated with modulation of nuclear factor-kappaB, and steroid hormone receptors. 1570 37

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors activated by specific ligands. PPARs play an important role in carcinogenesis, inflammation, atherosclerosis, lipid metabolism and diabetes. There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest, apoptosis and induction of differentiation, although the detailed signalling pathways have not been completely elucidated to date. The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability, proliferation, differentiation, apoptosis and expression of some cell cycle related proteins in glial tumor cell lines. The study was performed on human glioblastoma cell lines U-87 MG, T98G, A172 and U-118 MG. Cell lines were treated by ligands of PPARalpha (bezafibrate, gemfibrozil) and PPARgamma (ciglitazone). MTT, flow cytometry, TUNEL assay and immunoblotting were used for detection of changes in cell viability, proliferation, differentiation and apoptosis. Bezafibrate, ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines. The synthetic ligands significantly reduced or induced the expression of cyclins, p27Kip1, p21Waf1/Cip1, MDM-2, Bcl-2, Bax, PARP, Caspase 3, androgen receptors, etc. and did not affect the expression of the differentiation marker GFAP. Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial. Apart from hypolipidemic and hypoglycaemic effects, PPAR ligands may also have significant cytostatic effects of potential use in anticancer treatment.
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PMID:Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. 1580 Jul 11

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