Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoCl2)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP > PC-3 > PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoCl2-simulated hypoxia. CoCl2 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with CoCl2. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5-fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by CoCl2 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by CoCl2 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoCl2-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and sustained elevation of PGE2 synthesis in a human metastatic prostate cancer cell line, and suggest that COX-2 activity, reflected by PGE2 production, is involved in hypoxia-induced VEGF expression, and thus, modulates prostatic tumor angiogenesis.
Clin Exp Metastasis 1999
PMID:Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line. 1091 14

Cyclooxygenase-2 (COX-2) is an immediate early response gene that can be induced by a variety of tumor promoters, cytokines, growth factors and hypoxia. COX-2 overexpression is linked to all stages of carcinogenesis with the enzyme localized to the neoplastic cells, microvascular endothelial cells, and stromal fibroblasts. The contributions of COX-2 in tumor angiogenesis include: (a) the increased expression of the proangiogenic growth factor VEGF; (b) the production of the eicosanoid products thromboxane A2, PGE2 and PGI2 that can directly stimulate endothelial cell migration and growth factor-induced angiogenesis; and potentially, (c) the inhibition of endothelial cell apoptosis by stimulation of Bcl-2 or Akt activation. Selective pharmacological inhibitors of COX-2 as angiosuppressive agents could have therapeutic benefit in the treatment of neoplastic disease from prevention through treatment of advanced metastatic disease. These agents are safe and well tolerated and can be added to chemotherapy and radiation therapy where angiogenesis inhibitors appear to provide at least additive therapeutic benefit.
Cancer Metastasis Rev 2000
PMID:The contributions of cyclooxygenase-2 to tumor angiogenesis. 1119 Oct 59

Cyclooxygenase-2 (COX-2) is up-regulated in 85-90% of primary human colorectal cancers and is a putative target for the chemopreventative activity of non-steroidal anti-inflammatory drugs. However, COX-2 expression by human colorectal cancer liver metastases has been poorly characterized. We studied a consecutive series of 38 patients who underwent liver resection for metastatic disease, for whom long-term (up to 57 months), prospective follow-up data were available. Semi-quantitative immunohistochemistry for COX-2 was performed on 54 metastases from 35 patients, for whom adequate histological material was available. Diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastases (COX-2 score 1, n = 25; score 2, n = 29). There was no relationship between metastasis size or differentiation grade and the level of COX-2 protein expression. There was no difference in colorectal cancer-free or overall survival between patients with high (score 2) and low (score 1) COX-2 scores (Kaplan-Meier survival analysis and log rank test, both P = 0.97). Multivariate Cox regression analysis identified age, incomplete resection and presence of extra-hepatic disease as independent predictors of disease-free and overall survival following surgery. COX-2 protein was also localized to a subset of stromal fibroblasts and mononuclear cells within metastases as well as hepatocytes from resection specimens. COX-2 protein was expressed by cancer cells in all human colorectal cancer liver metastases which were studied. Investigation of the effect of selective COX-2 inhibition on metastasis growth and metastasis cancer cell proliferation/apoptosis in vivo are warranted.
Clin Exp Metastasis 2000
PMID:Cyclooxygenase-2 expression in colorectal cancer liver metastases. 1120 34

Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of different tumors, including those of the colon, pancreas, lung, and head and neck. We used in situ hybridization with a digoxgenin-labeled COX-2 antisense riboprobe to assess the presence of strong or intermediate versus weak or absent COX-2 expression in specimens from 160 patients with stage I non-small cell lung cancer (NSCLC). Of these, 3 specimens had strong expression, 69 had intermediate expression of COX-2, 24 had weak expression, and 64 had no detectable COX-2. The strength of COX-2 expression was associated with a worse overall survival rate (P = 0.001) and a worse disease-free survival rate (P = 0.022). The median survival times for the strong, intermediate or weak, and null COX-2 expressors were 1.04, 5.50, and 8.54 years, respectively. Interestingly, all three specimens with strong COX-2 expression came from patients who died within 18 months. Retinoic acid receptor beta (RAR-beta) is a nuclear retinoid receptor whose expression is frequently lost in aerodigestive tract carcinogenesis. We previously demonstrated that expression of RAR-beta in stage I NSCLC indicates a poor prognosis. Retinoids have been shown to prevent induction of COX-2 by mitogens and tumor promoters. Expression of COX-2 correlated with RAR-beta expression (P = 0.053), but not with k-ras mutational status, vascular endothelial growth factor, basic fibroblast growth factor, interleukin 8 levels, or other markers of angiogenesis, invasion, and metastases. Thus, like RAR-beta positivity, COX-2 overexpression appears to portend a shorter survival among patients with early stage non-small cell lung cancer. Future studies of RAR-beta and COX-2 regulation in NSCLC should further the development of prevention and therapy interventions with retinoids and/or COX-2 antagonists in this patient population.
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PMID:Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. 1130 34

Cyclooxygenase-2 (COX-2) has been suggested to be associated with carcinogenesis. In hepatocellular carcinoma (HCC), the expression pattern of COX-2 protein has been well correlated with the differentiation grade, suggesting that abnormal COX-2 expression plays an important role in hepatocarcinogenesis. We investigated the expression pattern and clinical significance of COX-2 in HCC tissues. In addition, we evaluated the efficacy of a selective COX-2 inhibitor, NS-398, in three hepatoma cell lines. Thirty-six HCC tissues, 15 hepatoma cell lines, 1 colorectal cell line (HT-29), and 1 fibroblast cell line (SV80) were included in the study. We evaluated serological tests and histological and radiological evaluations of HCC tissues. Immunohistochemical staining for COX-2 was performed on 36 HCC tissues and 17 cancer cell lines. A cell viability assay for growth inhibition of NS-398 in five cell lines was performed. Immunohistochemically, all six well-differentiated HCCs were positive, whereas 83% (10 of 12) of the poorly differentiated HCCs were negative. There was no significant relationship between the intensity of COX-2 expression and the level of alpha-fetoprotein, tumor size, presence of portal vein thrombosis, tumor capsule and metastasis, Tumor-Node-Metastasis staging, and growth types (P > 0.05). According to the cell viability assay, NS-398 suppressed the growth of all cell lines, independent of the degree of COX-2 expression. The inhibitory effect on each cell line was identified in 10 microM NS-398 and was significantly strong in 100 microM NS-398. All cell lines exhibited apoptosis, which was identified by 4'-6-diamidino-2-phenylindole staining. In conclusion, COX-2 may be a determinant of the differentiation grade of HCC, and the inhibition of COX-2 can induce growth suppression of hepatoma cell lines via induction of apoptosis.
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PMID:Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. 1135 Aug 71

Cyclooxygenase-2 (Cox-2) expression can induce mammary tumorigenesis in transgenic mice, and selective Cox-2 inhibitors are both chemopreventive and chemotherapeutic in rat models of breast cancer. We analyzed the expression of Cox-2 protein by immunohistochemistry in tissue array specimens of 1576 invasive breast cancers. Moderate to strong (elevated) expression of Cox-2 protein was observed in 37.4% of the tumors, and it was associated with unfavorable distant disease-free survival (P < 0.0001). Elevated Cox-2 expression was associated with a large tumor size, a high histological grade, a negative hormone receptor status, a high proliferation rate (identified by Ki-67), high p53 expression, and the presence of HER-2 oncogene amplification (P < 0.0001 for all comparisons), along with axillary node metastases and a ductal type of histology (P = 0.0001 and P = 0.0017, respectively). Interestingly, association with the unfavorable outcome was especially apparent in the subgroups defined by estrogen receptor positivity, low p53 expression, and no HER-2 amplification (P < 0.0001 for all comparisons). These results indicate that elevated Cox-2 expression is more common in breast cancers with poor prognostic characteristics and is associated with an unfavorable outcome. The present findings support efforts to initiate clinical trials on the efficacy of Cox-2 inhibitors in adjuvant treatment of breast cancer.
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PMID:Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. 1183 May 10

Colorectal cancer (CRC) is the second most common fatal malignancy in the Western world, with more than 150,000 new cases accounting for 55,000 deaths in the United States every year. Surgical resection is an effective treatment for localized disease, achieving a 5-year survival rate of 90%; but chemotherapy and other novel treatments for metastatic disease remain ineffective. There have been significant efforts to identify risk factors associated with the development of CRC and to explore potential preventive therapies. Both genetic and epigenetic factors contribute to the development of colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of CRC. Cooperative genetic aberrations involving APC (adenomatous polyposis coli), beta-catenine, K-ras, and p53 are involved in the multistep adenoma-carcinoma sequence of CRC. Emerging data have implicated cyclooxygenase-2 (COX-2) and prostanoid production in the pathogenesis of colorectal carcinoma. Several reports indicate a close relation between the intake of nonsteroidal antiinflammatory drugs (NSAIDs) and a decreased risk for developing colorectal cancer. Epidemiologic studies indicate a 40% to 50% reduction in mortality due to colorectal cancer in individuals taking NSAIDs (e.g., aspirin). Epigenetic factors including age, diet, angiogenesis, and immune responses also appear to contribute to the development of CRC. Combining knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of CRC. These developments may yield benefits in earlier detection and in the design of better antitumor interventions.
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PMID:New strategies for colorectal cancer prevention and treatment. 1194 69

Cyclooxygenase-2 (COX-2) is the enzyme that normally synthesizes prostaglandins during an inflammatory response. Many primary and metastatic cancers express COX-2, and its presence is correlated with tumor angiogenesis, more invasive tumor phenotype, resistance to apoptosis, and systemic immunosuppression. The expression of COX-2 is associated with a worse prognosis. Inhibition of prostaglandin synthesis may be beneficial in human malignancy. Regular consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of, and mortality rate resulting from, a number of types of gastrointestinal cancers. Premalignant colonic lesions regress following the administration of nonspecific COX inhibitors, such as sulindac (Clinoril). Advanced solid tumor patients treated with indomethacin (Indocin) survive twice as long as do such patients who receive supportive care alone. The U.S. Food and Drug Administration has approved specific COX-2 inhibitors for the treatment of arthritis, pain, and familial adenomatous polyposis. Preclinical studies show that these drugs block angiogenesis, suppress solid tumor metastases, and slow the growth of implanted gastrointestinal cancer cell lines. The COX-2 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies. Ongoing clinical trials are currently assessing the potential therapeutic role of COX-2 inhibitors in both prevention and treatment of a diverse range of human cancers.
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PMID:Celecoxib with chemotherapy in colorectal cancer. 1201 63

Adenocarcinoma of the mammary gland is the leading type of cancer in women. Among these breast cancers those that are estrogen-responsive respond well to existing therapeutic regimens while estrogen non-responsive cancers metastasize widely, demonstrate a high relapse rate, and respond poorly to therapy. Over-expression of the arachidonic acid-metabolizing enzymes cyclooxygenase-2 and lypoxygenases is frequently observed in breast cancer, particularly the non-estrogen-responsive type, suggesting a role of the arachidonic acid (AA) cascade in the growth regulation of these malignancies. Adenocarcinomas of the lungs, pancreas and colon also frequently over-express AA-metabolizing enzymes, and recent evidence suggests that the growth-regulating AA-cascade in these malignancies is under beta-adrenergic control. Our current experiments have therefore tested the hypothesis that in analogy to these findings adenocarcinomas of the breast are also regulated by beta-adrenergic receptors via stimulation of the AA-cascade. Analysis of DNA synthesis by [3H]-thymidine incorporation assays in three estrogen-responsive and three estrogen non-responsive cell lines derived from human breast cancers demonstrated a significant reduction in DNA synthesis by beta-blockers and inhibitors of cyclooxygenase or lipoxygenases in all cell lines. Analysis of AA-release in one of the most responsive cell lines demonstrated a time-dependent increase in AA-release in response to the beta-adrenergic agonist isoproterenol. Analysis by RT-PCR revealed expression of beta2-adrenergic receptors in all cell lines whereas beta1-adrenergic receptors were not found in two of the estrogen non-responsive cell lines. Our data suggest that a significant subset of human breast cancers is under control of beta-adrenergic receptors via stimulation of the AA-cascade. These findings open up novel avenues for the prevention and clinical management of breast cancer, particularly the non-estrogen-responsive types. Moreover, our findings suggest that cardiovascular disease and adenocarcinomas in a variety of organ systems, including the breast may share common risk factors and benefit from similar preventive and treatment strategies.
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PMID:Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. 1206 62

Metabolism of arachidonic acid through cyclooxygenase, lipoxygenase, or P450 epoxygenase pathways leads to the formation of various bioactive eicosanoids. In this review, we discuss alterations in expression pattern of eicosanoid-generating enzymes found during prostate tumor progression and expound upon their involvement in tumor cell proliferation, apoptosis, motility, and tumor angiogenesis. The expression of cyclooxygenase-2, 12-lipoxygenase, and 15-lipoxygenase-1 are up-regulated during prostate cancer progression. It has been demonstrated that inhibitors of cyclooxygenase-2, 5-lipoxygenase and 12-lipoxygenase cause tumor cell apoptosis, reduce tumor cell motility and invasiveness, or decrease tumor angiogenesis and growth. The eicosanoid product of 12-lipoxygenase, 12(S)-hydroeicosatetraenoic acid, is found to activate Erkl/2 kinases in LNCaP cells and PKCalpha in rat prostate AT2.1 tumor cells. Overexpression of 12-lipoxygenase and 15-lipoxygenase-1 in prostate cancer cells stimulate prostate tumor angiogenesis and growth, suggesting a facilitative role for 12-lipoxygenase and 15-lipoxygenase-1 in prostate tumor progression. The expression of 15-lipoxygenase-2 is found frequently to be lost during the initiation and progression of prostate tumors. 15(S)-hydroxyeicosatetraenoic acid, the product of 15-lipoxygenase-2, inhibits proliferation and causes apoptosis in human prostate cancer cells, suggesting an inhibitory role for 15-lipoxygenase-2 in prostate tumor progression. The regulation of prostate cancer progression by eicosanoids, in either positive or negative ways, provides an exciting possibility for management of this disease.
Cancer Metastasis Rev 2001
PMID:Role of eicosanoids in prostate cancer progression. 1208 62


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