环氧化酶—2在肿瘤新生血管生成中的调节作用

环氧化酶（COX）在多种肿瘤中有较高的表达，并认为其与前列腺素共同作用参与了该疾病状态下 的血管生成。本文综述环氧化酶与肿瘤新生血管生成之间的联系。     

环氧化酶2促肿瘤血管生成研究进展

近年来研究表明，环氧化酶(cyclooxygenase,COX)亚型COX-2表达在肿瘤的发生、发展、分化和转移中起重要作用，特别是参与肿瘤血管生成。全文主要综述了COX-2促进肿瘤血管生成的机制。     

环氧化酶-2在非小细胞肺癌的表达及与肿瘤血管生成的研究

目的　为探讨COX 2对非小细胞肺癌发生发展的影响 ,我们对肺癌患者与肺部良性疾病患者肺组织中COX 2表达情况进行了比较 ,并研究了COX 2与肺癌临床病理特征的关系及对肿瘤血管生成的影响。方法　免疫组化检测非小细胞肺癌COX 2表达、血管内皮生长因子 (VEGF)表达 ,并测定肿瘤微血管密度 (MVD)。结果　非小细胞肺癌组织COX 2蛋白阳性表达率为 69.2 % (5 4/78) ,显著高于良性对照组织的14 .3 % (2 /14 ) (χ2 =15 .0 44 ,P <0 .0 1)。COX 2表达阳性组MVD计数 (19.41± 8.5 6)显著高于COX 2表达阴性组 (12 .0 0± 5 .3 7) (t=3 .90 6,P <0 .0 1)。COX 2表达与肺癌患者性别、年龄、吸烟史及TNM分期无明显关系 (P >0 .0 5 ) ;在不同肿瘤的病理类型中 ,腺癌组织COX 2表达率为 88.9% (3 2 /3 6) ,显著高于鳞癌的5 0 .0 % (2 0 /4 0 ) (χ2 =13 .2 62 ,P <0 .0 1) ;鳞癌组织中低分化癌组织表达率为 81.0 % (17/2 1) ,显著高于中高分化癌组织的 15 .8% (3 /19) (χ2 =16.942 ,P <0 .0 1) ;腺癌组织中低分化癌组织表达率为 10 0 .0 % (18/18) ,显著高于中高分化癌组织的 77.8% (14 /18) (χ2 =6.0 46,P <0 .0 5 )。相关关系分析显示肺癌COX 2表达与VEGF表达呈显著正相关 (r =0 .5 0 9,P <0 .0 1) ;VEGF表达与MVD呈     

环氧化酶-2与肿瘤关系的研究进展

环氧化酶-2(COX-2)是体内前列腺素(PG)合成过程中重要的限速酶,在多种人类肿瘤中有不同程度的表达,并且与肿瘤发生、肿瘤细胞增殖、凋亡、肿瘤新生血管形成以及肿瘤的转移等有关.选择性COX-2抑制剂有望成为有效的肿瘤预防和治疗的新靶点.     

环氧化酶-2对鼻咽癌血管生成及预后的影响

Objective： The purpose of this study was to evaluate cyclooxygenase-2 （COX-2） expression in nasopharyngeal carcinoma （NPC） and its correlation with clinicopathologic features, angiogenesis, and prognosis. Methods： The expressions of COX-2 and vascular endothelial growth factor （VEGF） and microvascular density （MVD） were determined with immunohistochemical methods in eighty-six NPC patients followed up over 5 years. Results： Sixty-three tumors （73.3%） were classified as COX-2 positive. COX-2 expression was positively related to VEGF expression （r=0.438, P〈0.01） and correlated with the tumor pathological grade, extent of primary lesion, lymph node metastasis, distant metastasis and shorter survival. Conclusion： Our results suggest that COX-2, being highly expressed and strongly correlated with angiogenesis in nasopharyngeal carcinoma, is apt to be used as a predictor of prognosis, including local recurrence and distant metastasis.     

环氧化酶-2与肿瘤

环氧化酶 - 2是前列腺素 (PGs)生物合成过程中的一个重要的诱导酶 ,静息时不表达 ,当细胞受到各种刺激时 ,便可迅速合成。肿瘤组织中可有环氧化酶 - 2表达上调 ,并通过引起突变 ,抑制凋亡与促进粘附 ,引起细胞周期调节紊乱 ,促进浸润与转移 ,增加血管生成 ,减低免疫监视机能而参与肿瘤的发生与发展。     

喉癌中环氧化酶-2和血管生成素-2的表达及其相关性

目的 研究COX-2和Ang-2在喉癌中的表达及其相关性.方法 应用免疫组织化学SP法检测65例喉癌组织及34例癌旁阴性喉黏膜组织中COX-2和Ang-2的表达.并结合相关临床病理参数进行分析.结果 COX-2和Ang-2蛋白在喉癌组织中的阳性表达率分别为63.08%和69.23%,均高于癌旁喉黏膜组织中的表达(P<0.05).C0X-2及Ang-2的表达都与T分期和临床分期相关,且两者表达呈显著正相关性(P<0.05).Kaplan-Meier分析显示COX-2阳性表达和阴性表达组患者无瘤生存率和总生存率差异有统计学意叉,但Ang-2表迭仅影响患者的总生存率(P<0.05).结论 COX-2与Ang-2在喉癌表达异常增高,且呈正相关表达,其可能通过促进血管生成在肿瘤的形成、浸润、扩散等过程中发挥着重要作用,两者可作为判断喉癌生物学行为和预后的重要指标.     

环氧化酶-2与肿瘤关系的研究进展

环氧化酶-2(COX-2)是体内前列腺素(PG)合成过程中重要的限速酶，在多种人类肿瘤中有不同程度的表达，并且与肿瘤发生、肿瘤细胞增殖、凋亡、肿瘤新生血管形成以及肿瘤的转移等有关。选择性COX-2抑制剂有望成为有效的肿瘤预防和治疗的新靶点．     

环氧化酶-2、血管内皮生长因子在乳腺癌组织中表达及其对血管生成的影响

目的研究环氧化酶-2（COX-2）、血管内皮生长因子（VEGF）在乳腺癌组织中的表达，并探讨其对血管生成的作用。方法应用免疫组织化学SP法检测30例乳腺癌组织标本和20例正常乳腺组织标本中COX-2、VEGF的表达，并用血管内皮细胞标记物CD34单克隆抗体标记行免疫组织化学染色，观察肿瘤微血管生成状况。结果COX-2在70．0％（21／30）乳腺癌组织中过表达，VEGF在56．7％（17／30）乳腺癌组织中过表达，与正常组织相比差异均有统计学意义；COX-2和VEGF表达相关；COX-2和VEGF表达均与肿瘤微血管生成相关。结论COX-2和VEGF过表达均与乳腺癌血管生成有关。     

环氧化酶-2与肿瘤

环氧化酶-2在基因结构、表达调控及定位分布等方面都不同于环氧化酶-1.近几年来,流行病学、动物实验、细胞学实验等方面的证据表明,环氧化酶-2参与了肿瘤的发生与发展.本文在阐明环氧化酶-2与肿瘤的基本关系的基础上,力求反映其新近的研究进展.     

An immunohistochemical study of cyclooxygenase (COX)-2 expression in endocrine tumors of the pancreas

Cyclooxygenase (COX) is a key rate-limiting enzyme in prostaglandin biosynthesis. There are two isoforms of COX, referred to as COX-1 and COX-2. COX-2, an inducible form of COX, is found to be overexpressed in various neoplasms and is believed to play an important role in tumorigenesis and tumor development. In this study, we investigated expression of the COX-2 protein in human endocrine tumors of the pancreas (N=23; 6 insulinomas, one glucagnoma, 2 gastrinomas, and 14 non-functioning tumors) using immunohistochemistry. Strong COX-2 expression was confirmed in normal islet tissue as previously reported. COX-2 immunoreactivity was detected in 65% (15 out of 23) of these tumors with a moderate to strong intensity. In all nine functioning tumors, COX-2 expressions were preserved with the weak or strong intensity. In contrast, COX-2 was present in 6 out of 14 nonfunctioning tumors. The correlation between COX-2 expression and their function was significant (p<0.05). We found that expression of this enzyme was detected in 11 out of 15 benign tumors and in 4 out of 8 malignant tumors, respectively. Our results suggest that COX-2 may play an important role in the endocrine function of islet tumors. Additionally, malignancy was not related to COX-2 expression.     

Effect of inflammation on cyclooxygenase (COX)-2 expression in benign and malignant oesophageal cells

Chronic inflammation has been linked to carcinogenesis in various tissue sites. Barrett's oesophageal epithelium (BE) is a premalignant condition in which cyclooxygenase-2 (COX-2) levels are increased. However, it is not clear whether the primary stimulus for the high COX-2 levels is related to inflammation or malignancy. The effect of exogenous cytokines (IL-1beta, IL-10 and IL-13) on COX-2 expression was assessed by western blotting in three BE cancer cell lines (SEG-1, BIC-1 and OE33) and a squamous cancer cell line (OE21). Primary tissue was assessed from 17 patients with long BE segments, 13 oesophagitis, 30 oesophageal adenocarcinoma (EAC), and 40 normal oesophageal (NE) and duodenal (DU) controls. COX-2 protein expression was determined by western blotting and its tissue localization was examined using immunohistochemistry. COX-2 protein and the neutrophil marker myeloperoxidase (MPO) were quantified along BE segments. The leukocyte marker CD45 was used to identify any correlation between COX-2 expression and leukocyte cell distribution in EAC. IL-1beta induced COX-2 expression in SEG-1 cells (P < 0.05), whereas IL-10 and IL-13 had no effect. COX-2 protein levels were found to be increased in distal BE > proximal BE > oesophagitis > NE (P < 0.001). COX-2 expression in EAC was heterogeneous and the overall levels were not significantly increased. The increased COX-2 expression in distal BE was not associated with inflammation (MPO expression). In addition, there was no correlation between COX-2 and CD45 in AC. COX-2 protein expression in the oesophagus appears to be independent of the degree of inflammation.     

Selective inhibition of cyclooxygenase (COX)-2 inhibits endothelial cell proliferation by induction of cell cycle arrest

High-level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. Selective inhibition of COX-2 was shown to reduce colorectal tumorigenesis in different models of carcinogenesis and to prevent metastasis in xenograft tumor models, as well as to suppress in vitro induced angiogenesis. Recently, COX-2 was reported to be expressed not only in malignant epithelial cells, but also in the neovasculature that feeds the tumor in a variety of solid human cancers. Thus, one of the possible mechanisms by which selective COX-2 inhibitor reduces tumor growth and metastasis is through inhibition of tumor angiogenesis. Although a report suggested a possible role of endothelial COX-1 in the process of angiogenesis, in a recent study, the selective inhibition of COX-2 was shown to strongly inhibit angiogenesis by inducing endothelial cell (EC) apoptosis. In the present study, using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the potential antiangiogenic effect of the selective COX-2 inhibitor and its mechanism of action, and clearly demonstrated that selective inhibition of COX-2 caused a dose-dependent decrease in the proliferative activity of ECs, as well as an inhibition of capillary-like tube formation. The inhibitory effect on EC proliferation was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis.     

Selective cyclooxygenase (COX)-1 or COX-2 inhibitors control metastatic disease in a murine model of breast cancer

Using a highly metastatic mammary tumor cell line that expresses both cyclooxygenase (COX) isoforms, we now show that oral administration of either a selective COX-2 inhibitor (celecoxib) or a selective COX-1 inhibitor (SC560) to mice with established tumors results in significant inhibition of tumor growth. Administration of the dual inhibitor, indomethacin, leads to even better growth control. Metastatic capacity is also reduced by treatment of tumor-bearing mice with either COX-1 or COX-2 selective inhibitors. Pretreatment of tumor cells with COX inhibitors also reduces metastatic success, indicating that tumor cells may be a direct target of action by COX inhibitors. Growth of a second cell line, which does not express COX-2 in vivo, is also reduced by celecoxib, implicating both COX-dependent and COX-independent mechanisms.     

Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis

Nonsteroidal anti-inflammatory drugs are widely reported to inhibit carcinogenesis in humans and in rodents. These drugs are believed to act by inhibiting one or both of the known isoforms of cyclooxygenase (COX). However, COX-2, and not COX-1, is the isoform most frequently reported to have a key role in tumor development. Here we report that homozygous deficiency of either COX-1 or COX-2 reduces skin tumorigenesis by 75% in a multistage mouse skin model. Reduced tumorigenesis was observed even though the levels of stable 7,12-dimethylbenz(a)anthracene-DNA adducts were increased about 2-fold in the COX-deficient mice compared with wild-type mice. The premature onset of keratinocyte terminal differentiation appeared to be the cellular event leading to the reduced tumorigenesis because keratin 1 and keratin 10, two keratins that indicate the commitment of keratinocytes to differentiate, were expressed 8-13-fold and 10-20-fold more frequently in epidermal basal cells of the COX-1-deficient and COX-2-deficient mice, respectively, than in wild-type mice. Papillomas on the COX-deficient mice also displayed the premature onset of keratinocyte terminal differentiation. However, loricrin, a late marker of epidermal differentiation, was not significantly altered, suggesting that it was the early stages of keratinocyte differentiation that were primarily affected by COX deficiency. Because keratin 5, a keratin associated with basal cells, was detected differently in papillomas of COX-1-deficient as compared with COX-2-deficient mice, it appears that the isoforms do not have identical roles in papilloma development. Interestingly, apoptosis, a cellular process associated with nonsteroidal anti-inflammatory drug-induced inhibition of tumorigenesis, was not significantly altered in the epidermis or in papillomas of the COX-deficient mice. Thus, both COX-1 and COX-2 have roles in keratinocyte differentiation, and we propose that the absence of either isoform causes premature terminal differentiation of initiated keratinocytes and reduced tumor formation.     

Inhibition of cyclooxygenase (COX)-2 expression by Tet-inducible COX-2 antisense cDNA in hormone-refractory prostate cancer significantly slows tumor growth and improves efficacy of chemotherapeutic drugs.

PURPOSE: Overexpression of the proinflammatory enzyme cyclooxygenase (COX)-2 is associated with the progression of various malignancies; the role of COX-2 in prostate cancer is less clear. The significance of COX-2 in prostate cancer growth and response to chemotherapy was investigated in an androgen-refractory prostate cancer cell line using a Tet-inducible antisense COX-2 expression system. EXPERIMENTAL DESIGN: An antisense COX-2 cDNA construct under the control of a doxycycline-inducible promoter was transfected into a prostate cancer cell line, PC-3ML. Modulations of cell growth, apoptosis, and chemosensitivity in the presence or absence of doxycycline were analyzed. Tumor incidence, growth rate, and response to two cytotoxic drugs, COL-3 [chemically modified tetracycline-3-(6-demethyl-6-deoxy-4-dedimethylamino-tetracycline)] and Taxotere (docetaxel), were investigated in tumor xenografts. Apoptotic incidences and tumor microvessel density in tumors were determined by immunohistochemistry. RESULTS: Conditional suppression of COX-2 in PC-3ML caused reduced cell proliferation, decreased levels of phosphorylated AKT, G(0)-G(1) arrest, and increased apoptosis and caspase-3 activity. Suppression of COX-2 increased Bax protein and decreased Bcl-x(L) protein in vitro. COX-2 antisense-expressing PC-3ML tumors showed a 57% growth delay compared with nontransfected or vector controls. Oral administration of COL-3 (40 mg/kg, oral gavage) or Taxotere (2.3 mg/kg, intraperitoneally; 3x per week) in tumor-bearing mice further slowed tumor growth (65% and approximately 94%, respectively). Compared with the control group, the occurrence of apoptosis in antisense COX-2 tumors was eight times higher, and the tumor microvessel density was three times lower. CONCLUSIONS: These results provide direct evidence that constitutive expression of COX-2 in prostate cancer has both angiogenic and cytoprotective functions. Suppression of tumor cell COX-2 is sufficient to enhance chemotherapy response in prostate cancer.     

Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer

Inflammation plays a key role in the development of colorectal cancers. We have investigated the relationship between PTGS2 (COX2) polymorphisms and colorectal cancer risk in a hospital based case-control study. We recruited 292 patients with colorectal cancer and 274 controls from new patients admitted to Bellvitge Hospital, Barcelona, Spain, from 1996 to 1998. Subjects responded to a questionnaire on risk factors. Genotypes of the eight more frequent polymorphisms of PTGS2 were determined. Two polymorphisms are located in the promoter sequence, one in the untranslated region of exon 1, one in exon 3, one in intron 5, two in the untranslated region of exon 10, and one downstream of the last polyadenylation (poly-A) signal. Associations were analysed with logistic regression models assuming a dominant effect for rare variants to increase statistical power. An association was detected between colorectal cancer and a polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01. A nearby polymorphism downstream of the last poly-A signal also showed a nonsignificant increase in risk (OR 2.17, 95% CI 0.99-4.78, P=0.05). Analysis of haplotypes confirmed that individuals with these variants were at increased risk of colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97-4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti-inflammatory drugs and risk of colorectal cancer were also explored.     

Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk

In the human colon, arachidonic acid is metabolized primarily by cyclooxygenase (COX) and arachidonate lipoxygenase (ALOX) to bioactive lipids, which are implicated in colon cancer risk. Several polymorphisms in ALOX and COX genes have been identified, including G-1752A, G-1699A and Glu254Lys in ALOX5; Gln261Arg in ALOX12; Leu237Met and Val481Ile in COX1; and C-645T and Val511Ala in COX2. Because of the significant role of arachidonic acid metabolism in colon cancer, we hypothesized that these polymorphisms could influence susceptibility to colon cancer. We addressed this hypothesis in African-Americans and Caucasians using colon cancer cases (n = 293) and hospital- (n = 229) and population-based (n = 304) control groups. Polymorphisms did not differ between the control groups (P > 0.05); thus, they are combined for all analyses presented. ALOX5 Glu254Lys and COX2 C-645T and Val511Ala allele frequencies differed between Caucasians and African-American controls (P < 0.001). The ALOX5 -1752 and -1699 polymorphisms were in linkage disequilibrium (P < 0.001) and associated with a decreased risk in Caucasians in ALOX5 haplotype analyses (P = 0.03). Furthermore, an inverse association was observed between A alleles at positions -1752 and -1699 of ALOX5 and colon cancer risk in Caucasians, but not in African-Americans. Caucasians with A alleles at ALOX5 -1752 had a reduced odds of colon cancer versus those with G alleles [odds ratio (OR) (GA versus GG), 0.63; 95% confidence interval (CI), 0.39-1.01; OR (AA versus GG), 0.33; 95% CI, 0.07-1.65, P(trend) = 0.02]. Similar results were observed for ALOX5 G-1699A [OR (GA versus GG), 0.59, 95% CI, 0.37-0.94; OR (AA versus GG), 0.27, 95% CI, 0.06-1.32, P(trend) = 0.01]. Statistically significant associations with colon cancer were not observed for the other polymorphisms investigated. We have shown for the first time that a haplotype containing ALOX5 G-1752A and G-1699A in a negative regulatory region of the promoter may influence colon cancer risk in Caucasians.     

Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: evidence for growth suppression by inhibiting COX-2 expression

Cyclooxygenase (COX)-2 is one of the rate-limiting enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Recent studies have shown enhanced expression of COX-2 in cancer cells of several tissues. We investigated the expression of COX-2 and prostaglandin (PG) E((2)) production in two human skin epidermal cancer cell lines: cutaneous squamous cell carcinoma, HSC-5, and eccrine carcinoma, EcCa. Both COX-2 expression and PGE((2)) production were significantly enhanced in cancer cell lines compared with the non-tumorigenic human keratinocyte cell line, HaCaT. In order to determine the role of COX-2 in the proliferation of HSC-5 and EcCa, the growth of untreated cells and cells transfected with COX-2 antisense oligonucleotide was compared using the MTT assay. Transfection with the antisense oligonucleotide suppressed COX-2 protein expression and significantly inhibited cell growth. The effect of a selective inhibitor of COX-2, NS398, was compared with the effect of the antisense oligonucleotide in order to see whether COX-2 expression and prostaglandins have selective effects on cell growth. COX-2 expression was unchanged by NS398 treatment, whereas NS398 inhibited cell growth to a certain extent. The degree of growth inhibition was greater with the antisense oligonucleotide than with NS398. Our findings indicate that COX-2 protein expression is enhanced in skin epidermal cancer cells and that COX-2 plays a pivotal role in regulating cell growth. Furthermore, inhibition of COX-2 expression had a more significant effect on growth suppression than inhibition of COX-2 catalytic activity, suggesting the existence of two different signal pathways via COX-2 in regulating cell growth.     

The dynamic roles of angiopoietins in tumor angiogenesis

Angiopoietin (Ang)-1 and -2, and mouse Ang-3/human Ang-4 are ligands of the receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie)-2. It is well established that the Ang-Tie-2 pathway is involved in tumor angiogenesis. However, the exact effects of angiopoietins on tumor angiogenesis are under debate. Experimental and clinical studies have demonstrated that increased expression of Ang-1 and -2 promotes or inhibits tumor angiogenesis, and correlates with a reduced or extended survival time of patients, and with a declined or improved clinical outcome. In general, these studies suggest that Ang-1 is a proangiogenic factor that promotes endothelial cell survival and tumor angiogenesis, especially in the presence of vascular endothelial growth factor; whereas Ang-2 destabilizes vasculature that leads to the initiation of angiogenesis or apoptosis of endothelial cells/vessel regression in the presence or absence of vascular endothelial growth factor, respectively, and that the cell-surface tethered Ang-3 displays antiangiogenic activity. Together, these results suggest that the Ang-Tie-2 functional axis is an attractive target for antiangiogenesis-based cancer therapy.