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

Carcinogenesis involves inactivation or subversion of the normal controls of proliferation, differentiation, and apoptosis. However, these controls are robust, redundant, and interlinked at the gene expression levels, regulation of mRNA lifetimes, transcription, and recycling of proteins. One of the central systems of control of proliferation, differentiation and apoptosis is retinoid signaling. The hRAR alpha nuclear receptor occupies a central position with respect to induction of gene transcription in that when bound to appropriate retinoid ligands, its homodimers and heterodimers with hRXR alpha regulate the transcription of a number of retinoid-responsive genes. These include genes in other signaling pathways, so that the whole forms a complex network. In this study we showed that simple, cause-effect interpretations in terms of hRAR alpha gene transcription being the central regulatory event would not describe the retinoid-responsive gene network. A set of cultured bladder-derived cells representing different stages of bladder tumorigenesis formed a model system. It consisted of 2 immortalized bladder cell lines (HUC-BC and HUC-PC), one squamous cell carcinoma cell line (SCaBER), one papilloma line (RT4), and 4 transitional cell carcinomas (TCC-Sup, 5637, T24, J82) of varying stages and grades. This set of cells were used to model the range of behaviors of bladder cancers. Relative gene expression before (constitutive) and after treatment with 10 microM all-trans-retinoic acid (aTRA) was measured for androgen and estrogen receptor; a set of genes involved with retinoid metabolism and action, hRAR alpha nd beta, hRXR alpha and beta CRBP, CRABP I and II; and for signaling genes that are known to be sensitive to retinoic acid, EGFR, cytokine MK, ICAM I and transglutaminase. The phenotype for inhibition of proliferation and for apoptotic response to both aTRA and the synthetic retinoid 4-HPR was determined. Transfection with a CAT-containing plasmid containing an aTRA-sensitive promoter was used to determine if the common retinoic acid responsive element (RARE)-dependent pathway for retinoid regulation of gene expression was active. Each of the genes selected is known from previous studies to react to aTRA in a certain way, either by up- or down-regulation of the message and protein. A complex data set not readily interpretable by simple cause and effect was observed. While all cell lines expressed high levels of the mRNAs for hRXR alpha and beta that were not altered by treatment with exogenous aTRA, constitutive and stimulated responses of the other genes varied widely among the cell lines. For example, CRABP I was not expressed by J82, T24, 5637 and RT4, but was expressed at low levels that did not change in SCaBER and at moderate levels that decreased, increased, or decreased sharply in HUC-BC, TCC-Sup and HUC-PC, respectively. The expression of hRAR alpha, which governs the expression of many retinoid-sensitive genes, was expressed at moderate to high levels in all cell lines, but in some it was sharply upregulated (TCC-Sup, HUC-PC and J82), remained constant (5637 and HUC-BC), or was down-regulated (SCaBER, T24 and RT4). The phenotypes for inhibition of proliferation showed no obvious relationship to the expression of any single gene, but cell lines that were inhibited by aTRA (HUC-BC and TCC-Sup) were not sensitive to 4-HPR, and vice versa. One line (RT4) was insensitive to either retinoid. Transfection showed very little retinoid-stimulated transfection of the CAT reporter gene with RT4 or HUC-PC. About 2-fold enhancement transactivation was observed with SCaBER, HUC-BC, J82 and T24 cells and 3-8 fold with 5637, TCC-Sup cells. In HUC-BC, a G to T point mutation was found at position 606 of the hRAR alpha gene. This mutation would substitute tyrosine for asparagine in a highly conserved domain. These data indicate that retinoid signaling is probably a frequent target of inactivation in bladder carcinogenesis. (ABSTRAC
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PMID:Complexity, retinoid-responsive gene networks, and bladder carcinogenesis. 1059 47

We previously reported that cyclooxygenase (COX)-2 was predominantly expressed in macrophages of human colonic adenomas (Int. J. Cancer 83, 470-475.). The role of prostaglandins (PGs) produced by COX-2-expressing macrophages in colon carcinogenesis is still unclear. Here we show that PGs up-regulate vascular endothelial growth factor (VEGF) production by activated macrophages through their specific receptors. mRNAs of both PGE-specific receptors and peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, were expressed in phorbol 12-myristate 13-acetate-differentiated U937, a human macrophage model (H-Mac). Prostaglandin E(1) (PGE(1)) and 15-deoxy-Delta(12,14)-PGJ(2) (a potent PPARgamma ligand, 15d-PGJ(2)) dramatically increased VEGF production. The combination of PGE(1) and 15d-PGJ(2) additively increased VEGF production. In addition, PGE(1) significantly increased cAMP formation, whereas 15d-PGJ(2) did not affect cAMP formation. The effect of the combination of PGE(1) and 15d-PGJ(2) on cAMP formation was similar to that of PGE(1) alone. Unexpectedly, 15d-PGJ(2) also drastically increased IL-1beta production, an indicator of macrophage activation, although PGE(1) only mildly increased it. Additional enhancement of IL-1beta production was observed in the combination of PGE(1) and 15d-PGJ(2). These results suggest that PGs dramatically increased VEGF production by activated macrophages through specific PGE receptor and PPARgamma-mediated processes and that PGs may thereby promote tumor growth through VEGF production.
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PMID:Prostaglandins up-regulate vascular endothelial growth factor production through distinct pathways in differentiated U937 cells. 1087 32

Estrogens are important for the development of the mammary gland and strongly associated with oncogenesis in this tissue. The biological effects of estrogens are mediated through the estrogen receptor (ER), a member of the nuclear receptor superfamily. The estrogen/ER signaling pathway plays a central role in mammary gland development, regulating the expression and activity of other growth factors and their receptors. The generation of the ER knockout (ERKO) mouse has made it possible to directly understand the contribution of ER in mammary development and has provided an unique opportunity to study estrogen action in carcinogenesis. A mammary oncogene (Wnt-1) was introduced into the ERKO background to determine if the absence of the ER would affect the development of tumors induced by oncogenic stimulation. The development, hyperplasia, and tumorigenesis in mammary glands from the ERKO/Wnt-1 mouse line are described. These studies provide the impetus to evaluate the effect of other oncogenes in mammary tumorigenesis in the absence of estrogen/ER signaling.
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PMID:Mammary gland development and tumorigenesis in estrogen receptor knockout mice. 1093 20

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor and transcription factor that regulates the expression of many genes relevant to carcinogenesis, is now an important target for development of new drugs for the prevention and treatment of cancer. Deficient expression of PPARgamma can be a significant risk factor for carcinogenesis, although in some cases overexpression enhances carcinogenesis. Ligands for PPARgamma suppress breast carcinogenesis in experimental models and induce differentiation of human liposarcoma cells. By analogy to the selective estrogen receptor modulator (SERM) concept, it is suggested that selective PPARgamma modulators (SPARMs), designed to have desired effects on specific genes and target tissues without undesirable effects on others, will be clinically important in the future for chemoprevention and chemotherapy of cancer.
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PMID:Prospects for prevention and treatment of cancer with selective PPARgamma modulators (SPARMs). 1153 Mar 34

The gamma isoform of the peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that regulates adipocyte differentiation. Recently it has been shown to be expressed in human colonic mucosa and cancer, but its role in colon carcinogenesis and progression is still unclear. We demonstrate that activation of PPARgamma by ciglitazone (cig), a selective PPARgamma ligand, induces HT-29 human colon cancer cells to undergo apoptosis. Treatment with cig also down-regulates expression of cyclooxygenase-2 (COX-2) protein. Simultaneous exposure of cells to cig and 9-cis-retinoic acid (9-cis-RA), a ligand for retinoid X receptor, results in an increased apoptotic effect and increased inhibition of COX-2 expression, compared with cells treated with either cig or 9-cis-RA alone. As COX-2 is overexpressed in human colon cancer and has been implicated in augmenting invasiveness and tumorigenecity, the ability of PPARgamma activation to decrease COX-2 expression and induce apoptosis suggests that the PPARgamma pathway may be considered as a therapeutic target for colon cancer.
Carcinogenesis 2001 Sep
PMID:Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. 1153 58

Cyclooxygenase-2 (COX-2) is the inducible isoform of cyclooxygenase, the enzyme that catalyzes the rate-limiting step in prostaglandin synthesis from arachidonic acid. Various prostaglandins are produced in a cell type-specific manner, and they elicit cellular functions via signaling through G-protein coupled membrane receptors, and in some cases, through the nuclear receptor PPAR. COX-2 utilization of arachidonic acid also perturbs the level of intracellular free arachidonic acid and subsequently affects cellular functions. In a number of cell and animal models, induction of COX-2 has been shown to promote cell growth, inhibit apoptosis and enhance cell motility and adhesion. The mechanisms behind these multiple actions of COX-2 are largely unknown. Compelling evidence from genetic and clinical studies indicates that COX-2 upregulation is a key step in carcinogenesis. Overexpression of COX-2 is sufficient to cause tumorigenesis in animal models and inhibition of the COX-2 pathway results in reduction in tumor incidence and progression. Therefore, the potential for application of non-steroidal anti-inflammatory drugs as well as the recently developed COX-2 specific inhibitors in cancer clinical practice has drawn tremendous attention in the past few years. Inhibition of COX-2 promises to be an effective approach in the prevention and treatment of cancer, especially colorectal cancer.
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PMID:Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. 1185 43

The members of the nuclear receptor superfamily are known to mediate a wide array of basic biological processes, such as regulation of cell growth and differentiation, and induction of apoptosis. In several human malignancies, this central control function of nuclear receptors is disturbed, which seems to play an important role in tumor development and progression. Many nuclear receptor genes have been reported to be downregulated in malignancies; however, only a few mutations, gene arrangements, deletions or similar genetic changes have been shown to occur in these tumors. During the last decade, increasing attention has been directed towards epigenetic mechanisms of gene regulation such as DNA methylation. Many nuclear receptor genes can be silenced through aberrant methylation in tumors; epigenetic silencing, therefore, represents an additional mechanism that modifies expression of key genes during carcinogenesis. This review will give insights into the role of DNA methylation in the silencing of nuclear receptor genes and its involvement in human malignancies.
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PMID:DNA methylation of nuclear receptor genes--possible role in malignancy. 1186 59

Peroxisome proliferator activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARgamma is expressed at high levels in adipose tissue and plays a central role in adipocyte differentiation. Recent studies have implicated PPARgamma in the pathogenesis of several human malignancies. Here we review the evidence that PPARgamma contributes to prostate carcinogenesis and the potential for PPARgamma as a novel therapeutic target for prostate cancer.
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PMID:Peroxisome proliferator-activated receptor gamma (PPargamma) as a novel target for prostate cancer. 1209 79

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor superfamily and mediates most of the known biological effects of peroxisome proliferators. The latter represents a large group of chemicals that include the fibrate hyperlipidemic drugs, the pthalate plasticizers, various solvents and degreasing agents, and endogenous hormones and fatty acids. Peroxisome proliferators are classical members of the nongenotoxic group of chemical carcinogens that do not require metabolic activation to electrophiles in order to exert their harmful effects. These chemicals are of particular concern to regulatory agencies since they can only be detected by long-term carcinogen bioassays using rodents. The mechanism of the carcinogenic action of peroxisome proliferators is beginning to emerge. PPARalpha-null mice are resistant to hepatocarcinogenesis indicating that this receptor is necessary for cancer. However, recent studies indicate that Kupffer cells, in a PPARalpha independent manor, are required for the major effects of peroxisome proliferators on cell proliferation. An interaction between PPARalpha and estrogen carcinogenesis has also been elucidated.
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PMID:The peroxisome proliferator-activated receptor alpha (PPARalpha): role in hepatocarcinogenesis. 1216 Oct 4

Certain dietary retinoids and polyunsaturated fatty acids (PUFAs) consistently inhibit progression of mammary carcinogenesis both in animal studies and cell culture, but clinically, their effect is inconsistent. New evidence of synergistic interaction between the nuclear receptors for the two groups of nutritional agents suggests that appropriate selective ligands from each group might be combined in breast cancer chemoprevention studies. Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that is activated by PUFAs, eicosanoids and antidiabetic agents such as troglitazone. Such activation can cause growth inhibition in human mammary cancer cells in culture and the effect is enhanced by ligands of retinoic acid receptor (RAR) and retinoid X receptor (RXR). In mouse mammary tissue in organ culture, an RXR-selective ligand has been shown to enhance the effect of troglitazone in suppressing carcinogen-induced pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour growth inhibition and has been shown to bind directly to nuclear oestrogen response elements (ERE) independently of oestrogen receptor (ER) activity. A combination of an RXR-selective retinoid with either troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term study in postmenopausal women after primary surgery for intraductal breast cancer. The resulting activation of PPAR/RXR expression may increase response to retinoid administration, especially in the presence of obesity and insulin resistance, because of the ability of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I) concentrations. Serial core biopsies of breast tissue over a short term are proposed to identify changes in phenotype, which may influence progression to invasiveness. In addition to cytomorphological criteria, expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor in the nucleus should be examined.
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PMID:Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention. 1219 57


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