UMLS:C1326912 - FACTA Search

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Query: UMLS:C1326912 (tumorigenesis)
57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A considerable amount of evidence collected from several different experimental systems indicates that cyclooxygenase-2 (COX-2) may play a role in colorectal tumorigenesis. Large epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in persons taking aspirin or other nonsteroidal antiinflammatory drugs on a regular basis. One property shared by all of these drugs is their ability to inhibit COX, a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. In this study, we selected two transformed human colon cancer cell lines for studies on the role of COX-2 in intestinal tumorigenesis. We evaluated HCA-7 cells which express high levels of COX-2 protein constitutively and HCT-116 cells which lack COX-2 protein. Treatment of nude mice implanted with HCA-7 cells with a selective COX-2 inhibitor (SC-58125), reduced tumor formation by 85-90%. SC-58125 also inhibited colony formation of cultured HCA-7 cells. Conversely, SC-58125 had no effect on HCT-116 implants in nude mice or colony formation in culture. Here we provide evidence that there may be a direct link between inhibition of intestinal cancer growth and selective inhibition of the COX-2 pathway.
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PMID:Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. 915 99

Cyclooxygenase-2 (COX-2) expression is up-regulated in several types of human cancers and has also been directly linked to carcinogenesis. To investigate the role of COX-2 in pancreatic cancer, we evaluated COX-2 protein expression in primary human pancreatic adenocarcinomas (n = 23) and matched normal adjacent tissue (n = 11) by immunoblot analysis. COX-2 expression was found to be significantly elevated in the pancreatic tumor specimens compared with normal pancreatic tissue. To examine whether the elevated levels of COX-2 protein observed in pancreatic tumors correlated with the presence of oncogenic K-ras, we determined the K-ras mutation status in a subset of the tumors and corresponding normal tissues. The presence of oncogenic K-ras did not correlate with the level of COX-2 protein expressed in the pancreatic adenocarcinomas analyzed. These observations were also confirmed in a panel of human pancreatic tumor cell lines. Furthermore, in the pancreatic tumor cell line expressing the highest level of COX-2 (BxPC-3), COX-2 expression was demonstrated to be independent of Erk1/2 activation. The lack of correlation between COX-2 and oncogenic K-ras expression suggests that Ras activation may not be sufficient to induce COX-2 expression in pancreatic tumor cells and that the aberrant activation of signaling pathways other than Ras may be required for up-regulating COX-2 expression. We also report that the COX inhibitors sulindac, indomethacin and NS-398 inhibit cell growth in both COX-2-positive (BxPC-3) and COX-2-negative (PaCa-2) pancreatic tumor cell lines. However, suppression of cell growth by indomethacin and NS-398 was significantly greater in the BxPC-3 cell line compared with the PaCa-2 cell line (P = 0.004 and P < 0.001, respectively). In addition, the three COX inhibitors reduce prostaglandin E(2) levels in the BxPC-3 cell line. Taken together, our data suggest that COX-2 may play an important role in pancreatic tumorigenesis and therefore be a promising chemotherapeutic target for the treatment of pancreatic cancer.
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PMID:Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. 1065 49

Cyclooxygenase-2 (COX-2) gene overexpression is suggested to play important roles in colorectal tumorigenesis. Epidemiological studies revealed that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and sulindac, which inhibit COX activity, reduce colorectal cancer mortality. Current investigations have focused on delineating the molecular mechanisms that regulate COX-2 gene expression and the roles of NSAIDs in cancer chemoprevention. COX-2 catalyzes the production of prostaglandins (PGs) from arachidonic acid (AA), generated by phospholipases A2 (PLA2s), a family of acyl esterases that cause the release of AA from cellular phospholipids. Pancreatic secretory PLA2 (sPLA2), via its receptor (sPLA2R), transcriptionally activates COX-2 gene expression in several cell types, although a specific transcription factor mediating COX-2 expression has not yet been identified. Here, we report that a transcription factor, CCAAT/enhancer-binding protein beta(C/EBPbeta), plays a critical role in sPLA2IB-induced, receptor-mediated COX-2 gene expression in MC3T3E1 and NIH3T3 cells. Furthermore, treatment of these cells with NSAIDs in the presence of sPLA2IB appears to potentiate the stimulatory effects on COX-2 mRNA and COX-2 protein expression and a concomitant elevation in PG production. Most significantly, NSAID treatment appears to drastically suppress the production of cytosolic PLA2 (cPLA2) mRNA. The lack of sPLA2IB, sPLA2IIA, and sPLA2V mRNA expression in both NIH3T3 and MC3T3E1 cells suggests that cPLA2 is the most likely enzyme that catalyzes the release of AA, the rate-limiting substrate of COX for the production of PGs. Our results suggest that: (a) sPLA2IB receptor-mediated COX-2 expression is mediated via C/EBPbeta; (b) NSAIDs in the presence of sPLA2IB potentiate the stimulatory effects of sPLA2IB on COX-2 mRNA expression; and (c) despite the apparent stimulation of COX-2 expression by NSAIDs, they strikingly deprive COX-2 of its substrate, AA, by suppressing cPLA2 mRNA expression. Both AA and PGs regulate many vital biological functions (e.g., motility and invasiveness) that are dysregulated in most cancer cells, and they have profound effects on cellular differentiation. Our results raise the possibility that deprivation of COX-2 of its substrate by the suppression of cPLA2 mRNA expression is an additional mechanism used by NSAIDs to inhibit tumorigenesis.
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PMID:Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. 1070 28

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

Cancer results from disturbances of cellular signal transduction and data processing at the genetic and epigenetic level. In the early phase of the disease these disturbances are mainly caused by environmental toxic agents, i.e. genotoxic and non-genotoxic carcinogens, whereas endogenous agents derived from dys-regulated metabolic reactions may take over this role at later stages, thereby leading to a state of 'genetic instability' and 'growth autonomy'. Among these metabolic reactions becoming dys-regulated in the course of tumorigenesis, eicosanoid biosynthesis from arachidonic acid seems to play a particular role. A steadily increasing body of evidence indicates a causal relationship between cancer development and an abnormal overexpression of eicosanoid-forming enzymes, i.e. cyclooxygenases and lipoxygenases, in a wide variety of human and animal tumors. This overexpression seems to result from disturbances of cellular signaling cascades such as the Ras-Raf-MAPkinase cascade due to oncogenic gene mutations. Presently, research is focussed on the proinflammatory enzyme cyclooxygenase-2 (COX-2) the pathological overexpression of which has been found to be related to key events of tumor promotion such as cellular hyperproliferation, inhibition of programmed cell death, and tumor angiogenesis. In the mouse skin model of multistage carcinogenesis COX-2-derived prostaglandin F(2alpha) has been indentified as an endogenous tumor promoter. Moreover, genotoxic byproducts of both cylooxygenase and lipoxygenase-catalyzed arachidonic acid metabolism (such as active oxygen species, free radicals etc.) are suspected to contribute to 'genetic instability' and thus to malignant progression of tumor cells. The enzymes of eicosanoid biosynthesis rank therefore among the most attractive targets for cancer chernoprevention. In fact, both nonsteroidal antiinflammatory drugs, i.e. non-specific COX inhibitors, and isozyme-specific COX-2 inhibitors have been shown to inhibit experimental and human cancer development, in the latter case in particular in the large bowel. Beside their role as indicators of neoplastic development eicosanoids may be also used as reporters of skin irritation. Based to this concept an in vitro test system for skin toxicity has been developed in which the release of arachidonic acid and interleukin-1alpha, i.e. two key mediators of acute inflammation, from a human keratinocyte cell line is measured. The excellent correlation found between this mediator release and the effects of various chemical irritants on human skin in vivo indicates that, in the near future, this and related methods may help to do without animal experiments in toxicological testing.
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PMID:A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. 1109 Sep 44

Recent studies suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit lung tumorigenesis under conditions that are immunosuppressive. We hypothesized that this inhibition of mouse lung tumorigenesis requires induction of apoptosis and inhibition of COX (cyclooxygenase)-1, COX-2, and the incidence of K-ras mutation. The NSAIDs used in this study include acetylsalicylic acid (ASA) that is anti-inflammatory with COX-1 and COX-2 inhibition and N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398) that is a specific COX-2 inhibitor. We have previously demonstrated that ASA (147 and 294 mg/kg diet) and NS398 (7 mg/kg diet) inhibited lung tumorigenesis by 31%, 44%, and 34%, respectively, in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-treated A/J mice. No difference in the incidence and types of K-ras mutations was found between the lung tumors treated with NNK and those treated with NNK/ASA and NNK/NS398. In NNK-treated mice, ASA (394 mg/kg diet) or NS398 significantly increased the apoptotic index, from 0.07 to 0.30 or to 0.33, respectively. ASA (294 mg/kg diet) and NS398 also inhibited the expression of COX-2. Finally, modulation of gene expression by NS398 and ASA (294 mg/kg diet) was determined using Atlas cDNA expression arrays. Expression of cyclin B2 was decreased and expression of Fas-L and BAD were increased in lung tissues treated with both NS398 and ASA. Treatment with NS398 also increased expression of p57kip2 and myosin. These genes modulated by NSAIDs may play a role in mediating the observed chemopreventive effects of the NSAIDs in the mouse lung. Our results demonstrate that lung tumor prevention with NSAIDs involve both the induction of apoptosis and the inhibition of COX-2 expression.
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PMID:Inhibition of COX-2 and induction of apoptosis: two determinants of nonsteroidal anti-inflammatory drugs' chemopreventive efficacies in mouse lung tumorigenesis. 1119 67

Squamous cell carcinoma is one of the most common cancers in humans and is also a frequently diagnosed neoplasm in dogs. Induction of cyclo-oxygenase-2 (COX-2), a key rate-limiting enzyme in prostaglandin biosynthesis, has been implicated in the oncogenesis of various cancers in humans, including squamous cell carcinomas. However, expression of COX-2 has not been reported in spontaneous squamous cell carcinomas of non-human species. Canine squamous cell carcinomas share several similarities with the human disease. Therefore, the objective of this study was to determine whether COX isoenzymes were expressed in naturally occurring cases of squamous cell carcinomas in dogs. Canine normal skin (n=4) and squamous cell carcinomas (n=40) were studied by immunohistochemistry and immunoblotting analysis using polyclonal antibodies selective for COX-1 or COX-2. COX-2 was strongly expressed by neoplastic keratinocytes in all cases of squamous cell carcinomas, whereas no COX-2 was detected in normal skin and in the non-neoplastic skin and oral mucosa included in the tumor tissue samples (p<0.01). Immunoblotting analysis confirmed the restricted expression of COX-2 (72,000--74,000 molecular weight doublet) in squamous cell carcinomas only. In contrast, faint COX-1 staining was found in normal skin and in squamous cell carcinomas. This study demonstrates for the first time that COX-2 is induced in canine squamous cell carcinomas, and provides a new model to investigate the role and regulation of COX-2 gene expression in naturally occurring squamous cell carcinomas. (J Histochem Cytochem 49:867-875, 2001)
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PMID:Expression of cyclo-oxygenase-2 in naturally occurring squamous cell carcinomas in dogs. 1141 Jun 11

This study was designed to investigate the expression and molecular signaling of cyclooxygenase-1 (COX-1) in cervical carcinomas. Real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis confirmed enhanced expression of COX-1 RNA, and protein in squamous cell carcinomas and adenocarcinoma of the cervix. COX-1 expression in all carcinoma tissues was associated with enhanced expression of COX-2 RNA and protein. The site of COX-1 expression was localized by immunohistochemistry to the neoplastic epithelial cells in all squamous cell carcinomas and adenocarcinomas studied. Minimal COX-1 immunoreactivity was detected in normal cervix. To explore events associated with COX-1 up-regulation, we developed a doxycycline-regulated expression system in HeLa (cervical carcinoma) cells. Overexpression of COX-1 in HeLa cells resulted in induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES) concomitant with increased prostaglandin E(2) (PGE(2)) synthesis. Treatment of HeLa cells overexpressing COX-1 with the dual COX enzyme inhibitor indomethacin or selective COX-2 inhibitor NS-398 significantly reduced PGE(2) synthesis. Indomethacin, but not NS-398, treatment abolished the up-regulation of expression of COX-2 and PGES in HeLa cells, suggesting that the observed up-regulation of COX-2 and PGES was mediated by COX-1-enzyme products. To assess whether enhanced PGE(2) synthesis after COX-1 induction would act in an autocrine/paracrine manner, we investigated the effect of COX-1 on the expression of the different isoforms of PGE(2) receptors (EP1-EP4). We found that the cAMP-linked PGE(2) receptors were significantly up-regulated by COX-1 overexpression coincident with enhanced cAMP responsiveness of these cells to exogenous PGE(2) ligand. Finally, overexpression of COX-1 was associated with enhanced expression of the angiogenic factors basic fibroblast growth factor, vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2. This up-regulation of angiogenic factor expression was abolished by indomethacin and partially reduced by NS-398. These data indicate that COX-1 up-regulation modulates the expression of factors that may act in an autocrine/paracrine manner to enhance and sustain tumorigenesis in neoplastic cervical epithelial cells. It is likely that similar mechanisms may act in vivo to modulate tumorigenesis of cervical carcinomas.
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PMID:Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1. 1180 91

Recent evidence suggests that prostanoids are an important participant in the pathobiology of gastric adenocarcinoma, but the location and identity of cells in tumor-adjacent gastric mucosa able to synthesize and/or bind specific prostanoids is not clear. Using probes for cyclooxygenase 1 and 2 mRNA and protein as well as for the EP family of PGE(2) receptors, we sought to define the biology of prostanoids in adjacent human gastric mucosa at the site of tumor invasion. In mucosa adjacent to an invasive gastric adenocarcinoma, expression of cyclooxygenase was prominent, with COX 1 primarily in mucosal T lymphocytes surrounding nests of tumor cells. Densitometry showed these tumor-adjacent cells had substantial levels of COX 1 immunoreactive protein (relative intensity, 3.2). Cyclooxygenase 2 was newly expressed among these cells as well, but was limited in number (<25% of cyclooxygenase-positive T lymphocytes) in tumor-adjacent mucosa. Further, CD3(+) mononuclear cells, adjacent to tumor, strongly expressed prostanoid receptor EP(4) (relative intensity, 8.0), but cells with this receptor were not evident in the tumor itself. In contrast, normal gastric mucosa showed a consistent and structured expression of cyclooxygenase and PGE(2) receptor immunoreactive protein among mucosal cells. Cyclooxygenase 1 and PGE(2) receptor EP(4) were expressed on mucosal CD3(+) T lymphocytes in the lumenal (upper) third of gastric mucosa; and prostanoid receptors EP(2), EP(3) and EP(4), on gastric epithelia lining gastric pits. In situ hybridization with COX cDNAs confirmed these findings, and neither COX 2-specific mRNA nor protein was detected in normal gastric tissue. Our studies suggest that synthetic machinery and receptors for PGE(2), prominently expressed by T lymphocytes in gastric mucosa at the boundary of normal mucosa with tumor cells, may play a central role in prostanoid-driven tumorigenesis of this tissue.
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PMID:PGE(2) receptors and synthesis in human gastric mucosa: perturbation in cancer. 1205 58

More than 10 years after its discovery, the function of cyclooxygenase-2 (COX-2) in the cardiovascular system remains largely an enigma. Many scholars have assumed that the allegedly detrimental effects of COX-2 in other systems (e.g. proinflammatory actions and tumorigenesis) signify a detrimental role of this protein in cardiovascular homeostasis as well. This view, however, is ill-founded. Recent studies have demonstrated that ischemic preconditioning (PC) upregulates the expression and activity of COX-2 in the heart, and that this increase in COX-2 activity mediates the protective effects of the late phase of PC against both myocardial stunning and myocardial infarction. An obligatory role of COX-2 has been observed in the setting of late PC induced not only by ischemia but also by delta-opioid agonists and physical exercise, supporting the view that the recruitment of this protein is a central mechanism whereby the heart protects itself from ischemia. The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE(2) and/or PGI(2). Since inhibition of iNOS in preconditioned myocardium blocks COX-2 activity whereas inhibition of COX-2 does not affect iNOS activity, COX-2 appears to be downstream of iNOS in the protective pathway of late PC. The results of these studies challenge the widely accepted paradigm that views COX-2 activity as detrimental. The discovery that COX-2 plays an indispensable role in the anti-stunning and anti-infarct effects of late PC demonstrates that the recruitment of this protein is a fundamental mechanism whereby the heart adapts to stress, thereby revealing a novel, hitherto unappreciated cardioprotective function of COX-2. From a practical standpoint, the recognition that COX-2 is an obligatory co-mediator (together with iNOS) of the protection afforded by late PC has implications for the clinical use of COX-2 selective inhibitors as well as nonselective COX inhibitors. For example, the possibility that inhibition of COX-2 activity may augment myocardial cell death by obliterating the innate defensive response of the heart against ischemia/reperfusion injury needs to be considered and is the object of much current debate. Furthermore, the concept that the COX-2 byproducts, PGE(2) and/or PGI(2), play a necessary role in late PC provides a basis for novel therapeutic strategies designed to enhance the biosynthesis of these cytoprotective prostanoids in the ischemic myocardium. From a conceptual standpoint, the COX-2 hypothesis of late PC expands our understanding of the function of this enzyme in the cardiovascular system and impels a critical reassessment of current thinking regarding the biologic significance of COX-2.
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PMID:Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. 1216 Sep 47

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