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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins and other eicosanoids have been studied extensively in their physical, biochemical, biophysical and pharmacological aspects. However, studies on their role in tumor progression, especially metastases are relatively recent. Following a brief overview of the history of discovery and metabolism of eicosanoids and other fatty acids, we discuss the functions of these fatty acids (with emphasis on prostacyclin, thromboxane A2, 12-hydroxyeicosatetraenoic acid and 13-hydroxyoctadecadienoic acid) in cell transformation, tumor promotion and particularly in tumor cell metastasis. The relation between these monohydroxy fatty acids and tumor cell metastasis is discussed from three different perspectives, i.e., their effects on tumor cells, on platelets and on endothelial cells. The mechanism of these effects are then addressed at cell adhesion molecule, motility, protease, cell cytoskeleton, protein kinase and eicosanoid receptor levels. Finally, regulation of three key enzymes which generate eicosanoids (phospholipase, prostaglandin endoperoxide synthase and lipoxygenase) is explored.
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PMID:Fatty acid modulation of tumor cell-platelet-vessel wall interaction. 142 24

Prostaglandins (PGs) and their analogs endoperoxides are a large series of compounds which mainly enhanced cancer development and progression, acting as cocarcinogens or tumor promoters, and having profound effects on carcinogenesis. Although PGs are ubiquitous tissue hormones exerting pleiotropic effects on cancer cells, their mechanism(s) of action at molecular and cellular levels are not yet elucidated. Autoradiographic, ultrastructural, antigenic, and cell surface studies revealed that PGs act namely by their specific receptors and by interfering with DNA, RNA and protein synthesis, cell membranes and cell communications. PGs also play a role in tumor immunology and transplantation, acting as immunomodulators. Prostaglandins exert their effects by autocrine and paracrine mechanisms similar to hormone-like substances, and hypophysectomy reduces some of their tumor-promoting effects. PGs may act synergistically with hormones, growth factors (GFs), and vitamins. Several drugs called PG-synthesis inhibitors or PG-antagonists are found to markedly inhibit the cyclooxygenase activity. Most of these PG-inhibitors (aspirin, ibuprofen, indomethacin, piroxicam, sulindac) or commonly called NSAIDs (nonsteroidal antiinflammatory drugs) also significantly inhibit cancer development and cancer progression, and are recently used in epidemiological studies for cancer prevention and treatment. Developing more active and less toxic NSAIDs, which can also more selectively inhibit PG synthesis, is a promising field in prostaglandin research.
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PMID:Prostaglandins, their inhibitors and cancer. 884 35

The purpose of Study 1 was to examine the effect of dietary soy on the progression of MDA-MB-435 human breast cancer cell solid tumors in nude mice. When toasted soy chips were fed at levels of 5%, 10%, or 20% (wt/wt) in a high-fat, linoleic acid-rich diet for 12 weeks, there was a trend for larger mammary fat pad tumors to occur with increasing soy intake. However, compared with the controls the severity of macroscopic lung metastasis was reduced significantly in the groups fed 10% and 20% soy. Study 2 compared the effects of diets containing 23% corn oil (CO), 18% menhaden oil (MO) + 5% CO, 18% MO + 5% CO + 10% soy chips, and MO or soy-supplemented diets + indomethacin treatment in the same animal model. Feeding the 18% MO diet without soy or indomethacin reduced primary tumor growth; statistically significant effects were not observed in any of the other groups. All three of the groups with MO supplementation showed a reduction in the occurrence and severity of macroscopic lung metastases, together with the expected decreases in tumor prostaglandin E levels. These effects were most pronounced when MO was combined with indomethacin treatment. When indomethacin was given with dietary soy, the previously reported suppressive effect of the cyclooxygenase inhibitor on MDA-MB-435 cell tumor progression was lost, despite reductions in tumor prostaglandin E concentrations.
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PMID:Effects of dietary menhaden oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth and metastasis in nude mice. 938 84

Human breast cancer cell lines growing as xenografts in athymic nude mice have been used to examine the effects of dietary fat and fatty acids on tumor progression. The estrogen independent MDA-MB-435 cell line has the advantage that it metastasizes consistently to the lungs and forms quantifiable secondary nodules when injected into the mammary fat pads. With these breast cancer cells, the stimulating effects of polyunsaturated omega-6 fatty acids on both primary tumor growth and metastasis were demonstrated; in contrast, the long-chain omega-3 fatty acids were inhibitory. The model can also be adapted to examine dietary fatty acids, and inhibitors of their metabolism, as experimental adjuvant therapy after surgical excision of the primary tumors. Unfortunately, estrogen dependent human breast cancer cells do not metastasize, or do so rarely, in nude mice; in consequence, it is not possible to use the model to study estrogen-fatty acid interactions on the metastatic process. In addition to metastasis from a primary location, intravenous injection of MDA-MB-435 cells into the nude mouse host, particularly when combined with studies using Matrigel-based in vitro invasion assays, permits further dissection of the steps in the metastatic cascade which are influenced by dietary fatty acids. The results obtained by these several approaches have demonstrated distinct roles for the cyclooxygenase and lipoxygenase-mediated products of omega-6 fatty acid metabolism, and suggest new approaches to experimental breast cancer therapy.
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PMID:Dietary fat and breast cancer metastasis by human tumor xenografts. 947 77

The effects of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine H-7 (a cAMP-dependent protein kinase and protein kinase C inhibitor), n-(2-[methylamino]ethyl)-5-isoquinoline-sulfonamide H-8 (a cAMP- and cGMP-dependent protein kinase inhibitor) and indomethacin (IND, a cyclooxygenase inhibitor) on both the spontaneous metastatic ability of 3LL (Lewis lung carcinoma) tumor cells and anti-tumor host response were studied. The study of tumor progression showed that H-7 and H-8 (2 mg kg(-1) day(-1) , i.p., for 8 days) significantly reduced the mean number of metastases (0.8 +/- 0.2 and 1.0 +/- 0.7, respectively, P < 0.05) with respect to the number of lung metastases (4.2 +/- 2.1) observed in the control group. In turn, the highest tumor-specific cytotoxicity response (50% increase vs. non-treated target cells) was observed when both animal and tumor cells were treated with H-8. This suggests that the protein kinase inhibitors could inhibit tumor progression toward lung metastases formation by blocking the immunosuppressor mechanism triggered by agents that increase intracellular cAMP.
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PMID:Effect of the protein kinase inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine H-7 and N-(2-[methylamino]ethyl)-5-isoquinoline-sulfonamide H-8 on Lewis lung carcinoma tumor progression. 972 36

The nonsteroidal antiinflammatory drug sulindac (sulfoxide) is known to cause regression and prevent recurrence of adenomas in patients with familial adenomatous polyposis. The mechanism of action does not appear to require inhibition of prostaglandin synthesis since the sulfone metabolite of sulindac (FGN-1) retains the antineoplastic properties of sulindac but lacks inhibitory effects on cyclooxygenase, types 1 and 2. FGN-1 has been shown to induce apoptosis in a variety of tumor cell lines, and selective apoptosis of neoplastic cells has been proposed to account for its antineoplastic properties. Since angiogenesis is necessary for tumor progression and may be related to apoptosis, it is possible that inhibition of angiogenesis may also contribute to the antineoplastic properties of sulindac or FGN-1. In order to test this possibility, cells derived from several different types of human lung tumors were grafted intradermally in Balb/c mice. Sulindac sulfoxide and its sulfide and sulfone metabolites were administered for 3 days orally, in a daily dose of 0.025-0.5 mg, and angiogenesis was measured after 72 h using a previously described method. The results showed that sulindac sulfoxide and sulfone statistically inhibited angiogenesis.
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PMID:Inhibition of angiogenesis by sulindac and its sulfone metabolite (FGN-1): a potential mechanism for their antineoplastic properties. 989 80

The role of nitric oxide (NO) in tumorigenesis is multifactorial. NO can participate in the complicated process of carcinogenesis by mediating DNA damage in early phases of tumorigenesis, as well as support tumor progression through the induction of angiogenesis and suppression of the immune response. This paper addresses the effects of NO on transcriptional regulation following DNA damage and cyclooxygenase expression in the multistep process of tumorigenesis.
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PMID:Role of nitric oxide in cancer biology. 1063 Jun 89

Mouse lung tumorigenesis is a convenient model for examining all stages of lung adenocarcinoma (AC) progression. Because enhanced cyclooxygenase 2 (COX-2) expression has been observed in advanced human AC, we investigated the intracellular concentrations of the two cyclooxygenases, cyclooxygenase 1 (COX-1) and COX-2, at different times after carcinogen administration to A/J mice. The concentrations of both proteins were much higher in urethane-induced adenomas and carcinomas compared with control A/J mouse lung tissue (P < 0.03 and P < 0.01 in adenomas and AC, respectively, for COX-1; P < 0.003 and P < 0.004 in adenomas and AC, respectively, for COX-2). Small benign tumors that arose spontaneously in 13-month-old mice also stained for COX-1 and COX-2, showing that this elevated enzyme content does not depend on chemical induction. COX-1 and COX-2 immunostaining was observed in normal bronchiolar and alveolar epithelia, alveolar macrophages and bronchiolar smooth muscle. This is the first report of the cellular distribution of COX-1 and COX-2 in murine lungs and the first in any species to demonstrate their co-localization. COX content in isolated bronchiolar Clara cells, a putative cell of tumor origin, was equal to that found in tumors, suggesting that the high enzyme content in neoplasms is due to their proportionally high concentration of these tumor precursor cells. Different patterns of COX-1 and COX-2 expression were observed in tumors of different growth patterns; only occasional small foci stained in solid adenomas, while most cells in papillary adenomas were immunoreactive. This staining pattern was also seen in adenocarcinomas, but some of the papillary portions also included focally stained and unstained regions. The continued expression during neoplastic progression of these specialized enzymes present in normal cells of tumor origin suggests their function in maintenance of the neoplastic state.
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PMID:High cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) contents in mouse lung tumors. 1075 83

Cyclooxygenase 2 (COX-2) overexpression has been described in sporadic colonic neoplasia, but its role in ulcerative colitis (UC) neoplastic progression remains unexplored. Although the specific role of cyclooxygenase in colonic neoplasia is uncertain, its inhibition by nonsteroidal anti-inflammatory drugs decreases the risk of sporadic colonic adenocarcinoma and causes regression of adenomas in familial adenomatous polyposis. To investigate the role of COX-2 in UC-associated neoplasia, we assessed COX-2 protein and mRNA expression throughout the spectrum of UC-associated neoplastic lesions in four total colectomy specimens, using immunocytochemistry and a novel TaqMan reverse transcriptase-polymerase chain reaction assay. The findings were correlated with DNA ploidy and inflammatory activity. We found COX-2 overexpression throughout the neoplastic spectrum in UC (P: < 0.0001, R:(2)=0.53), even in diploid samples that were negative for dysplasia. Overall, neoplastic change explained 53% of the variation in COX-2 expression, whereas inflammatory activity explained only 11%. COX-2 was overexpressed in all aneuploid samples and in 38% of diploid samples (P: = 0.0074). cDNA representational difference analysis was also performed and revealed that COX-2 mRNA was an up-regulated cDNA representational difference analysis difference product. COX-2 overexpression occurs early in UC-associated neoplasia, and the increase cannot be explained by inflammatory activity alone. The data suggest that COX-2-specific inhibitors may have a chemopreventative role in UC but the possibility that they could exacerbate UC inflammatory activity needs to be tested.
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PMID:The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. 1098 Jan 13

Epidemiological studies suggest an inverse relationship between the intake of dietary fiber, particularly fiber from cereal grains, and colon cancer risk. Animal model assays have demonstrated that the protective effects of dietary fiber on colon cancer development depend on the nature and source of the fiber. Wheat bran (WB) appears to inhibit colon tumorigenesis more consistently than do oat bran or corn bran. This study was designed to determine whether specific WB fractions such as WB fiber, WB lipids, or phytic acid differentially affect colon carcinogenesis in a well-established colon cancer model. In addition, the modulating effect of specific fractions of WB on the activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-1 and COX-2 enzymes were assessed in colon tumors as those have been shown to play a role in tumor progression. At 5 weeks of age, groups of male F344 rats were assigned to one of six diets: a high-fat diet containing 10% WB (control diet) and experimental high-fat diets containing 10% dephytinized WB (WB-P), 10% defatted WB (WB-F), 10% dephytinized and defatted WB (WB-PF), 10% WB-PF fortified with 2% bran oil and/or with 0.4% phytate. At 7 weeks of age, all eats except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight/week. They continued to receive their respective diets until 50 weeks after carcinogen treatment and were then killed. Colon tumors were analyzed for iNOS, COX-1, and COX-2 expression and enzymatic activities. Colon tumors were evaluated histopathologically and classified as adenomas and adenocarcinomas. We found that removal of phytic acid (WB-P) or lipids (WB-F) from WB had no significant effect on colon tumor incidence (% animals with tumors) or multiplicity (tumors/ animal), whereas removal of both phytate and lipids from WB (WB-PF) significantly increased colon tumor multiplicity and volume. Interestingly, WB-PF fortified with excess bran oil or with bran oil plus phytate significantly inhibited colon tumor incidence, multiplicity, and volume; but supplementation of WB-PF with phytate alone had no significant effect on colon tumorigenesis in rats suggesting that lipid fraction of WB possesses tumor-inhibitory properties. Moreover, feeding WB-PF diet significantly increased iNOS, total COX and COX-2 enzyme activities, and iNOS protein expression in colon tumors as compared with wheat bran control diet. Feeding the WB-PF that was fortified with excess bran oil alone or with bran oil plus phytate significantly suppressed the activities of iNOS and COX-2 as well as the expression of iNOS and COX-2 in colon tumors compared with that in rats fed the WB diet or WB-PF diet. The study demonstrates for the first time that the lipid fraction of wheat bran has strong colon tumor inhibitor properties. The exact mechanism(s) by which the lipid fraction of WB inhibits colon carcinogenesis in addition to alteration of iNOS and COX activities remains to be elucidated. Additional studies are warranted to identify biologically active constituents of lipid fraction of WB and their relative role in colon tumor inhibition.
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PMID:Preventive potential of wheat bran fractions against experimental colon carcinogenesis: implications for human colon cancer prevention. 1098 88


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