Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C1326912 (tumorigenesis)
57,481 document(s) hit in 31,850,051 MEDLINE articles (0.01 seconds)

Cyclooxygenase-2 (COX-2), the inducible COX isozyme, plays a key role in intestinal tumorigenesis. We have demonstrated recently that COX-2 protein is induced in the polyp stroma near the intestinal luminal surface in the Apc(Delta716) mouse, a model for human familial adenomatous polyposis, and stimulate tumor angiogenesis. However, the precise cell types that express COX-2 are still to be determined. By immunohistochemical analysis, here we show that the majority of COX-2-expressing cells in the intestinal polyps of Apc(Delta716) mice are fibroblasts and endothelial cells. Furthermore, the COX-2-expressing cells in human familial adenomatous polyposis polyps are also fibroblasts and endothelial cells. In contrast, bone marrow-derived cells such as macrophages and leukocytes express little COX-2 protein in the intestinal polyps. These results clearly indicate that fibroblasts and endothelial cells play important roles in polyp expansion by expressing COX-2, resulting in tumor angiogenesis.
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PMID:Cyclooxygenase-2 expression in fibroblasts and endothelial cells of intestinal polyps. 1246 Aug 97

Matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2) are expressed in both sporadic and familial adenomatous colonic polyps and tumours and have been independently shown to play causal roles in intestinal tumour formation in mouse models of colon cancer. The apparent roles of these enzymes in intestinal tumorigenesis led us to examine, in the Min mouse model of colon cancer, if selective COX-2 and MMP inhibitors provide additive or synergistic therapeutic benefits in intestinal tumour prevention. The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-2I) both showed dose-dependent inhibition of the number of adenomas in Min mice. Using suboptimal doses, the MMPI reduced tumour multiplicity by 32%, the COX-2I by 48% and, both agents in combination resulted in a 67% decrease compared to control demonstrating a cooperative effect on intestinal tumorigenesis. Apoptosis, proliferation, and angiogenesis were assayed in tumors from each treatment group. These agents in combination allowed for a lowered dosage to be administered to achieve significant biological effects. Clinically, this could potentially reduce side effects associated with currently used MMP and COX-2 inhibitors. Together, these compounds could represent an easily tolerated chemopreventive approach.
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PMID:Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction. 1277 76

It is clear that COX-2 plays an important role in tumor and endothelial cell biology. Increased expression of COX-2 occurs in multiple cells within the tumor microenvironment that can impact on angiogenesis. COX-2 appears to: (a) play a key role in the release and activity of proangiogenic proteins; (b) result in the production of eicosanoid products TXA2, PGI2, PGE2 that directly stimulate endothelial cell migration and angiogenesis in vivo, and (c) result in enhanced tumor cell, and possibly, vascular endothelial cell survival by upregulation of the antiapoptotic proteins Bcl-2 and/or activation of PI3K-Akt. Selective pharmacologic inhibition of COX-2 represents a viable therapeutic option for the treatment of malignancies. Agents that selectively inhibit COX-2 appear to be safe, and well tolerated suggesting that chronic treatment for angiogenesis inhibition is feasible [107-110]. Because these agents inhibit angiogenesis, they should have at least additive benefit in combination with standard chemotherapy [111] and radiation therapy [24, 112]. In preclinical models, a selective inhibitor of COX-2 was shown to potentiate the beneficial antitumor effects of ionizing radiation with no increase in normal tissue cytotoxicity [113-115]. More recently, metronomic dosing regimens of standard chemotherapeutic agents without extended rest periods were shown to target the microvasculature in experimental animal models and result in significant antitumor activity [116-118]. This antiangiogenic chemotherapy regimen could be enhanced by the concurrent administration of an angiogenesis inhibitor [116-119]. Trials that will evaluate continuous low dose cyclophosphamide in combination with celecoxib are underway in patients with metastatic renal cancer, and non-Hodgkin's lymphoma [120]. Given the safety and tolerability of the selective COX-2 inhibitors, and the potent antiangiogenic properties of these agents, the combination of antiangiogenic chemotherapy with a COX-2 inhibitor warrants clinical evaluation [118, 121, 122]. The effects of selective COX-2 inhibitors on angiogenesis may also be due, in part, to COX-independent mechanisms [123-125]. Several reports have confirmed COX-independent effects of celecoxib, at relatively high concentrations (50 microM), where apoptosis is stimulated in cells that lack both COX-1 and COX-2 [126]. More recently, Song et al. [127] described structural modifications to celecoxib that revealed no association between the COX-2 inhibitory and proapoptotic activities of celecoxib [125]. Some of the COX-independent mechanisms for NSAIDs and selective COX-2 inhibitors include activation of protein kinase G, inhibition of NF-kappa B activation, downregulation of the antiapoptotic protein Bcl-XL, inhibition of PPAR delta, and activation of PPAR gamma. One or more of these COX-independent effects could contribute to the antiangiogenic properties of NSAIDs and selective COX-2 inhibitors. In order to take advantage of both the COX-dependent and COX-independent benefits of NSAIDs and selective COX-2 inhibitors, will require evaluation of these agents in neoplastic disease settings, using cancer-specific biomarkers. In conclusion, the contribution of COX-2 at multiple points in the angiogenic cascade makes it an ideal target for pharmacologic inhibition. The reported success of selective COX-2 inhibitors in cancer prevention could be related to angiogenesis inhibition [109]. As premalignant lesions progress towards malignancy, there is a switch to the angiogenic phenotype that is subsequently followed by rapid tumor growth [128, 129]. Intervention with angiogenesis inhibitors at this early stage of carcinogenesis has been shown to attenuate tumor growth in transgenic mouse models [130, 131]. The continued dependence on angiogenesis for later stages of tumorigenesis suggests that COX-2 inhibitors also will have clinical utility in the management of advanced cancers.
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PMID:Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. 1279 55

The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is normally expressed predominantly in kidney and brain, and also has important roles in reproduction and inflammation. COX-2 misexpression has been observed in numerous human cancers, including the majority of colorectal cancers. Recently, COX-2 overexpression has been described in human breast cancer. COX-2 is present in about 40% of invasive breast carcinomas, particularly those that overexpress HER2/neu, and COX-2 expression correlates with poor patient prognosis. Manipulation of Cox-2 gene dosage by using transgenic overexpression and knockout approaches has revealed an important role for Cox-2 in tumorigenesis. Furthermore, translational experiments using rodent breast cancer models suggest COX-2 inhibition to be an effective strategy for both prevention and treatment of experimental breast cancers. Since COX-2 can contribute to multiple facets of tumorigenesis, including angiogenesis, several mechanisms are likely to underlie the anticancer action of COX inhibitors. Thus, selective COX-2 inhibitors offer considerable promise for the prevention and treatment of human breast cancer.
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PMID:COX-2 inhibitors for the prevention of breast cancer. 1458 62

To determine its effect on intestinal tumorigenesis and the protumorigenic COX pathway in Apc(Min/+) mice, resveratrol was administered as a powdered admixture in the diet at 0, 4, 20, or 90 mg/kg body weight for 7 wk. In two separate experiments, resveratrol did not affect intestinal tumor load. It was stable in the diet under experimental conditions, circulated in the plasma as the glucuronide-conjugated form and reached the tumors as evidenced by significant decreases in PGE2 levels. However, immunohistochemical staining of intestinal tumors revealed no changes in COX-2 expression. This study demonstrates that resveratrol consumed ad libitum in the diet, does not modify tumorigenesis in Apc(Min/+) mice.
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PMID:Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice. 1470 85

Cyclooxygenase-2 (COX-2) is an inducible enzyme that regulates prostaglandin synthesis and is overexpressed at sites of inflammation and in several epithelial cancers. Recently, a causal link for COX-2 in epithelial tumorigenesis was shown in genetically-manipulated animal models of colon and breast carcinoma. Data indicate that COX-2 is involved in the regulation of apoptosis, angiogenesis, and tumor cell invasiveness, which appear to contribute to its effects on tumorigenesis. Multiple studies have shown that nonselective COX and selective COX-2 inhibitors effectively prevent experimental colon cancer. Furthermore, sulindac and the selective COX-2 inhibitor celecoxib were shown to regress colorectal polyps in patients with familial adenomatous polyposis. Although the exact anti-tumor mechanisms of these agents await further study, data indicate that both COX-dependent and COX-independent mechanisms may be important. In this review, the association between COX-2 and colorectal tumorigenesis and potential mechanisms of this effect are discussed. Additionally, evidence supporting the role of NSAIDs and selective COX-2 inhibitors for the prevention and treatment of human colorectal cancer is reviewed.
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PMID:Role of cyclooxygenase-2 in colorectal cancer. 1500 Jan 50

Two isoforms of cyclooxygenase, COX-1 and COX-2, have been identified and shown to be involved in tumorigenesis. Although, overexpression of COX-2 in human cancers has been repeatedly reported, no data have hitherto been available for Thai patients. To cast light on the role(s) of COX enzymes in the development and progression of colorectal cancers and to determine the incidence of COX-2 overexpression, the expression levels of COX-1 and COX-2 proteins using Western blot analysis in tumor tissues and adjacent normal tissues obtained from 44 Thai patients with colorectal cancer. Compared with paired normal tissues, COX-2 was overexpressed in 13 of 44 colorectal tumor tissues (29.5%). Overall, COX-2 levels in colorectal tumor specimens were significantly correlated with histological differentiation, in particular in the tumors with poor differentiation (p<0.05). In addition, overexpression of COX-2 was found more frequently in colorectal tumors with lymphatic invasion, regional lymph node metastasis and larger size, although without statistical significance. In contrast to the relatively consistent alteration in COX-2 expression, the level of COX-1 expression was quite varied in tumor tissues. Forty-eight percent of colorectal tumors exhibited a decreased level of COX-1 in comparison to normal tissues and overexpressed in 23%. Thus both isoforms may both play roles in promoting tumorigenesis. However, there was no significant relationship between the alteration of COX-1 protein levels and any pathological features of tumors.
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PMID:Expression of cyclooxygenase-1 and -2 and clinicopathologic features of colorectal cancer in northern Thailand. 1507 4

Emerging reports now implicate alterations of arachidonic acid (AA) metabolism with prostate carcinogenesis. To test this hypothesis, androgen-primed benign hyperplastic (BHC) and malignant tumorigenic (MTC) cells derived from the Lobund-Wistar rat model of autochthonous prostate adenocarcinoma were incubated with (14)C-AA. Our data using MTCs revealed enhanced dual metabolism of (14)C-AA via COX to generate increased PGE(2) and via 5-lipoxygenase (LOX) to generate increased 5S-HETE in tumorigenic cells. Western blot of MTCs revealed upregulation of COX-2 expression. This paralleled the increased biosynthesis of PGE(2). Since some polyunsaturated fatty acids have been reported to modulate AA metabolism and tumorigenesis, we primed the cells with either gamma-linolenic acid (GLA) or its in vivo metabolite, 15S-HETrE, prior to incubation with AA. Our data revealed suppression of COX-2 expression/PGE(2) biosynthesis. In parallel, priming cells with 15S-HETrE resulted in greater suppression of COX-2 expression/PGE(2) biosynthesis. These findings suggest that 15S-HETrE could function in vivo after dietary intake of GLA to suppress DHT-enhanced prostatic COX-2 expression/PGE(2) biosynthesis and, thus, alleviate tumor growth and progression.
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PMID:Suppression of cyclooxygenase-2 overexpression by 15S-hydroxyeicosatrienoic acid in androgen-dependent prostatic adenocarcinoma cells. 1519 70

There is now substantial evidence for a role for cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) signalling during carcinogenesis in a number of tissues and selective COX-2 inhibitors (coxibs) were considered attractive candidate chemoprevention agents. However, recent concerns over the toxicity of systemic selective COX-2 inhibition and the realisation that COX-1 may also contribute to carcinogenesis have cast some doubt on COX-2 inhibition as a safe and effective chemoprevention strategy. This review will describe the available evidence relating to the known benefits (preventive efficacy in rodent tumorigenesis models and limited human data from small randomised, controlled trials and epidemiological studies) and risks (cardiovascular and renal toxicity) of coxib therapy for cancer chemoprevention. Potential, alternative strategies for inhibition of COX-PG signalling that minimise or avoid systemic selective COX-2 inhibition will also be discussed.
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PMID:Cyclooxygenase-2: how good is it as a target for cancer chemoprevention? 1600 78

There is strong evidence for an important role for increased COX (cyclo-oxygenase)-2 expression and PG (prostaglandin) E2 production in colorectal tumorigenesis. PGE(2) acts through four E-prostanoid receptors (EP1-4). COX-2 has therefore become a target for the potential chemoprevention and therapy of colorectal cancer. However, any therapeutic/preventive strategy has the potential to have an impact on physiological processes and hence result in side effects. General COX (COX-1 and -2) inhibition by traditional NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, although chemopreventive, has some side effects, as do some conventional COX-2-selective NSAIDs. As PGE2 is thought to be the major PG species responsible for promoting colorectal tumorigenesis, research is being directed to a number of protein targets downstream of COX-2 that might allow the selective inhibition of the tumour-promoting activities of PGE2, while minimizing the associated adverse events. The PGE synthases and E-prostanoid receptors (EP1-4) have therefore recently attracted considerable interest as potential novel targets for the prevention/therapy of colorectal cancer. Selective (and possibly combinatorial) inhibition of the synthesis and signalling of those PGs most highly associated with colorectal tumorigenesis may have some advantages over COX-2-selective inhibitors.
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PMID:Prospects in NSAID-derived chemoprevention of colorectal cancer. 1604 70


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