UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.02 seconds)

We have investigated the hypothesis that nitric oxide synthase (NOS2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) protein levels individually demonstrate a direct correlation with microvessel density (MVD) and clinical outcome in human non-small cell lung cancer (NSCLC). Furthermore, we hypothesized that MVD may explain the propensity of certain histological lung cancer subtypes for early metastasis via a hematological route. Immunohistochemically, we studied the protein expression levels of NOS2, COX2, and VEGF and MVD by counting CD31-reactive blood vessels (BVs) in 106 surgically resected NSCLC specimens. NOS2, COX2, and VEGF immunoreactivity were observed in 48, 48, and 58%, respectively, of the study subjects, and their levels correlated with MVD at the tumor-stromal interphase (P < or = 0.001). More adenocarcindmas and large cell carcinomas displayed overexpression of NOS2 when compared with squamous cell carcinoma (SCC; r = 0.44; P < 0.001). NOS2 and COX2 levels were found to correlate positively with VEGF status (r = 0.44; P < 0.001, 0.01, and 0.03, respectively). These results attest to the significant interaction of these factors in the angiogenesis of NSCLC. Although neither angiogenic factors nor MVD correlated with patient survival, the latter correlated with tumor clinical stage in both squamous (SCC; 73 BVs/mm2) and non-SCC (78 BVs/mm2) tumors. These results indicate that angiogenesis is a complex process that involves multiple factors including NOS2, COX2, and VEGF. Furthermore, the role of angiogenesis in the biology of various histological lung cancer types may be different. The complexity of angiogenesis may explain the modest results observed in antiangiogenesis therapy that target a single protein.
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PMID:Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma. 1115 8

Regular intake of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased incidence of colorectal, esophageal, gastric, and lung cancer. The relative risk of colorectal cancer is about 0.6 in large cohort studies--in other words, the risk is reduced by 40%. Also, in experimental models, the frequency of colonic cancer is reduced by NSAIDs. Both human and experimental tumors contain increased amounts of prostaglandin E(2), which may have a role in the accelerated proliferation taking place in tumor tissue. This may be the result of activation of cyclooxygenase-2 (COX-2) in response to mitogens and growth factors, for example, which will result in an increased production of prostaglandins. The current theory is that the mechanism for the suppressor effect of NSAIDs on carcinogenesis is COX-2 inhibition. However, reliable data on the dose of aspirin or other NSAIDs for optimal benefit for tumor suppression are lacking, and it is still premature to give general recommendations on using NSAIDs for chemoprevention of gastrointestinal cancer.
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PMID:Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract. Extent, mode, and dose dependence of anticancer effects. 1116 2

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.
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PMID:The contributions of cyclooxygenase-2 to tumor angiogenesis. 1119 Oct 59

Modulation of cyclooxygenase-2 (COX-2) mRNA stability plays an important role in the regulation of its expression by oncogenic Ras. Here, we evaluate COX-2 mRNA stability in response to treatment with two known endogenous promoters of gastrointestinal cancer, the bile acid (chenodeoxycholate; CD) and ceramide. Treatment with CD and ceramide resulted in a 10-fold increase in the level of COX-2 protein and a four-fold lengthening of the half-life of COX-2 mRNA. COX-2 mRNA stability was assessed by Northern blot analysis and by evaluating the AU-rich element located in the COX-2 3'-UTR. A known inhibitor of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK), PD98059, reversed the effects of CD or ceramide to stabilize COX-2 mRNA. Overexpression of a dominant-negative ERK-1 or ERK-2 protein also led to destabilization of COX-2 mRNA. Treatment with a p38 MAPK inhibitor, PD169316, or transfection with a dominant-negative p38 MAPK construct reversed the effect of CD or ceramide to stabilize COX-2 mRNA. Expression of a dominant-negative c-Jun N-terminal kinase (JNK) had no effect on COX-2 mRNA stability in cells treated with CD or ceramide. We conclude that posttranscriptional mechanisms play an important role in the regulation of COX-2 expression during carcinogenesis.
Neoplasia
PMID:Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells. 1122 45

Recent studies suggest that expression of cyclooxygenase-2 (Cox-2) is elevated in transitional cell carcinoma (TCC) of the urinary bladder and that inhibition of Cox-2 activity suppresses bladder cancer in experimental animal models. We have investigated the expression of Cox-2 protein in human TCCs (n = 85), in in situ carcinomas (Tis) of the urinary bladder (n = 17), and in nonneoplastic urinary bladder samples (n = 16) using immunohistochemistry. Cox-2 immunoreactivity was detected in 66% (67 of 102) of the carcinomas, whereas only 25% (4 of 16) of the nonneoplastic samples were positive (P: < 0.005). Cox-2 immunoreactivity localized to neoplastic cells in the carcinoma samples. The rate of positivity was the same in invasive (T1-3; 70%, n = 40) and in noninvasive (Tis and Ta; 65%, n = 62) carcinomas, but noninvasive tumors had a higher frequency (32%) of homogenous pattern of staining (>90% of the tumor cells positive) than the invasive carcinomas (10%) (P: < 0.05). However, several invasive TCCs exhibited the strongest intensity of Cox-2 staining in the invading cells, whereas other parts of the tumor were virtually negative. Finally, strong Cox-2 positivity was also found in nonneoplastic ulcerations (2 of 2) and in inflammatory pseudotumors (2 of 2), in which the immunoreactivity localized to the nonepithelial cells. Taken together, our data suggest that Cox-2 is highly expressed in noninvasive bladder carcinomas, whereas the highest expression of invasive tumors associated with the invading cells, and that Cox-2 may also have a pathophysiological role in nonneoplastic conditions of the urinary bladder, such as ulcerations and inflammatory pseudotumors.
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PMID:Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder. 1123 34

Recent studies have demonstrated that overexpression of cyclooxygenase-2 (COX-2) and elevation of COX-2-mediated synthesis of prostaglandin E(2) (PGE(2)) were observed in various cancers including esophageal cancer, but their roles in carcinogenesis of the esophagi still remain unclear. To address the issue, we observed the reduction of N:-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in rat esophagi via JTE-522 (4-[4-cyclohexyl-2-methyloxazol-5-yl]-2-fluorobenzenesulfonamide), a selective COX-2 inhibitor. In this study, 54 F344 male rats were divided into nine groups; JTE-522 (3, 9 and 30 mg/kg) was administered orally. We also examined the effects of JTE-522 on COX-2 mRNA and synthesis of PGE(2). In the group in which JTE-522 was administered intermittently at a daily dose of 30 mg/kg, the number of NMBA-induced esophageal tumors per rat significantly reduced, to 62% (P< 0.05), but the size of the tumors was not significantly inhibited. In the group in which JTE-522 was administered continuously five times weekly for 24 weeks at a daily dose of 9 mg/kg, both the number and size of tumors significantly reduced, to 29 and 44%, respectively (P<0.05). Furthermore, JTE-522 suppressed not only tumor formation but also developing carcinomas (P<0.0021) [corrected]. In this study, treatment with NMBA alone resulted in an approximately 5-fold rise in expression of COX-2 mRNA detected by semi-quantitative RT-PCR analysis and an approximately 7-fold increase in the production of PGE(2) measured by ELISA compared with the normal esophageal mucosa. The up-regulated COX-2 expression did not decrease with the treatment of JTE-522 at the 3, 9 and 30 mg/kg doses; however, the increased levels of PGE(2) synthesis were significantly decreased by administering JTE-522 (P<0.01). Our study suggests that COX-2-mediated PGE(2) is important in NMBA-induced esophageal tumorigenesis in rats, and therefore may be a promising chemotherapeutic target for the prevention and treatment of esophageal cancer, especially with selective COX-2 inhibitors.
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PMID:Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by JTE-522, a selective COX-2 inhibitor. 1128 87

Colorectal carcinogenesis is a complex, multistep process involving genetic alterations and progressive changes in signaling pathways regulating intestinal epithelial cell proliferation, differentiation, and apoptosis. Although cyclooxygenase-2 (COX-2), gastrin-releasing peptide (GRP), and its receptor, GRP-R, are not normally expressed by the epithelial cells lining the human colon, the levels of all three proteins are aberrantly overexpressed in premalignant adenomatous polyps and colorectal carcinomas of humans. Overexpression of these proteins is associated with altered epithelial cell growth, adhesion, and tumor cell invasiveness, both in vitro and in vivo; however, a mechanistic link between GRP-R-mediated signaling pathways and increased COX-2 overexpression has not been established. We report that bombesin, a homolog of GRP, potently stimulates the expression of COX-2 mRNA and protein as well as the release of prostaglandin E(2) from a rat intestinal epithelial cell line engineered to express GRP-R. Bombesin stimulation of COX-2 expression requires an increase in [Ca(2+)](i), activation of extracellular signal-regulated kinase (ERK)-1 and -2 and p38(MAPK), and increased activation and expression of the transcription factors Elk-1, ATF-2, c-Fos, and c-Jun. These data suggest that the expression of GRP-R in intestinal epithelial cells may play a role in carcinogenesis by stimulating COX-2 overexpression through an activator protein-1-dependent pathway.
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PMID:Activator protein-1 transcription factor mediates bombesin-stimulated cyclooxygenase-2 expression in intestinal epithelial cells. 1129 36

Over 15,000 human tumor p53 mutations have been recorded in the scientific literature, including over 700 mutations in esophageal tumors. There are no data on p53 mutations in esophageal cancer patients from Iran yet; however, this country experiences one of the highest cancer mortality rates in the world for esophageal squamous cell carcinomas (ESCCs). The causes of this high cancer burden in Iran remain obscure and do not appear to be related to tobacco and alcohol consumption, the two major risk factors identified in Europe and North America. Because molecular analysis of tumors can provide clues to endogenous or environmental factors contributing to high cancer risk, we examined 74 Iranian ESCCs for the presence of mutations in exons 5-8 of the p53 gene by PCR and direct sequencing. Forty-eight of the 74 tumors (65%) had one or more p53 gene point mutations, including 5 patients with two or more mutations and one with a tandem mutation in codon 242. Surprisingly, over one-third of the 54 mutations we identified were transitions at CpG sites (20 of a total of 54 mutations, or 37%), a class of mutation that is significantly less common (16% of mutations) in the compilation of ESCC mutations from other countries (chi2 statistic, P < 0.0002), whereas transversions, which the literature shows to be common in ESCCs from non-Iranian patients, were infrequent in the tumors we examined here. Elevated levels of cyclooxygenase-2 and inducible nitric oxide synthase were observed in 74 and 91%, respectively, of tumors from Tehran as determined by immunohistochemistry, and high COX-2 expression correlated significantly with the presence of a p53 mutation in the tumor. Mediators of the inflammatory response in esophageal mucosa, perhaps in conjunction with specific dietary or cultural practices in Iran, may contribute importantly to the p53 mutation load in Iranian ESCC patients.
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PMID:Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran. 1130 96

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

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown cancer preventive activity in patients who took them frequently. These drugs can induce tumor cells to undergo apoptosis in vitro. NS398, a cyclooxygenase-2 (COX-2)-selective inhibitor, has been reported to cause apoptosis in cancer cell lines. Therefore, we examined its effect on 15 human colon cancer cell lines and investigated its mechanism of action. NS398 decreased cell viability in all of the cell lines. Tumor cells that expressed COX-2 were shown to be more sensitive to NS398 treatment. In three selected colon cancer cell lines, NS398-induced apoptosis was mediated by the release of cytochrome c from mitochondria and, consequently, by the activation of caspase-9 and caspase-3 and by the cleavage of poly(ADP-ribose) polymerase. In contrast, caspase-8 was not involved in NS398-induced apoptosis, which suggested that the cytochrome c pathway may play an important role in NS398-induced apoptosis in colon cancer cell lines. Therefore, the combination of NS398 with apoptosis-inducing drugs through cytochrome c-independent pathways may be warranted.
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PMID:Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway. 1130 52

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