Microvessel density is a prognostic marker of human gastric cancer

INTRODUCTIONGastric cancer is one of the most frequent and lethal malignancies worldwide, especially in Eastern Asia including China, and the 5-year survival rate is only about 20%[1]. A recent research has shown an increasing trend of gastric cancer mortality in China in the past 20 years, especially in rural areas and among aged people[2]. To date, the treatment outcome of this common malignancy is still not satisfactory. One major difficulty in the diagnosis and treatment of gastric c…     

Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer

Angiogenesis is a key prerequisite for the successful establishment, growth, and dissemination of tumors. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity and cyclooxygenase-2 (COX-2) promotes angiogenesis by modulated production of angiogenic factors including VEGF. The current study was designed to investigate the possible roles of COX-2 and VEGF in gastric cancer angiogenesis. In this study, we conducted an immunohistochemical investigation of COX-2 and VEGF expression in 97 patients with gastric cancer. To assess tumor angiogenesis, microvessel density (MVD) was determined by CD34 immunohistochemical staining. Expression of COX-2 and VEGF in gastric cancer tissues, was demonstrated in 63.9% and 75.3% of cases, respectively. The expression of COX-2 correlated significantly with VEGF expression. High MVD was significantly associated with depth of tumor invasion and poor survival. The mean MVD value of VEGF positive tumors was 79.8 +/- 32.0 and significantly higher than that of VEGF negative tumors. The mean MVD value of COX-2 positive tumors was 77.9 +/- 29.9 and not significantly higher than that of COX-2 negative tumor. The mean value of MVD in tumors positive for both COX-2 and VEGF was significantly higher than that in tumors negative for both. However, there was no correlation between COX-2 or VEGF expression and various clinicopathological features including patient survival. These results suggest that COX-2 may play an important role in carcinogenesis by stimulating tumor angiogenesis in concert with VEGF in human gastric cancer.     

Inflammation in lung carcinogenesis: new targets for lung cancer chemoprevention and treatment

Lung carcinogenesis is a complex process involving the acquisition of genetic mutations that confer cancer development and the malignant phenotype, and is critically linked to apoptosis resistance, unregulated proliferation, invasion, metastasis, and angiogenesis. Epithelial mesenchymal transition (EMT) in cancer is an unregulated process in a host environment with deregulated inflammatory response that impairs cell-mediated immunity and permits cancer progression. Given the immunosuppressive tumor environment, strategies to reverse these events by stimulating host immune responses are an important area of investigation. Cyclooxygenase 2 (COX-2) and its downstream signaling pathways are potential targets for lung cancer chemoprevention and therapy. Clinical trials are underway to evaluate COX-2 inhibitors as adjuvants to chemotherapy in patients with lung cancer and to determine efficacy in prevention of bronchogenic carcinoma. The understanding of molecular mechanisms involved in inflammation and lung carcinogenesis provide insight for new drug development that target reversible, non-mutational events in the chemoprevention and treatment of lung cancer.     

Role of cyclooxygenase-2 in gastric cancer development and progression

Although the incidence of gastric cancer has been declining in recent decades,it remains a major public health issue as the second leading cause of cancer death worldwide.In China,gastric cancer is still the main cause of death in patients with malignant tumors.Most patients are diagnosed at an advanced stage and mortality is high.Cyclooxygenase-2(COX-2)is a ratelimiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer.The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated.Helicobacter pylori infection,tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer.The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells,while inhibiting apoptosis,assisting angiogenesis and lymphatic metastasis,and participating in cancer invasion and immunosuppression.This review is intended to discuss,comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression,and elucidate the molecular mechanisms which might be involved in the carcinogenesis.     

RUNX3基因在肺癌中的表达及与肺癌血管生成的关系

目前在世界范围内,肺癌已占据所有癌症病死率的首位。随着放疗、靶向治疗、免疫治疗等各种新型治疗方法的出现,寻找某种生物标记物对肺癌指导治疗及评估预后显得十分迫切。人类RUNT相关转录因子3（RUNX3）基因是新近发现的一种抑癌基因,目前认为RUNX3在肺癌细胞中表达下降甚至沉默,并与肿瘤的血管生成关系密切。本文就RUNX3基因表达与肺癌血管生成的关系作一综述。     

Cyclooxygenase-2 expression is associated with well-differentiated and intestinal-type pathways in gastric carcinogenesis

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) expression appears to be increased in several different types of human cancers, suggesting that the presence of COX-2 is associated with carcinogenesis. Recently, increased expression of COX-2 has been frequently detected in gastric cancer, and this may have prognostic significance. In the present study, we aimed to analyze the expression of COX-2 in a much larger sample to determine whether COX-2 expression is related to the clinicopathological features and survival rates of patients with gastric cancer. METHODS: We investigated 140 patients with gastric cancer who underwent surgery between January 1992 and December 1993 and examined the expression of COX-2 in human gastric cancer tissue by immunohistochemistry. RESULTS: COX-2 expression was present in the cytoplasm of tumor cells but not in normal gastric epithelia. Positive expression of COX-2 was detected in 86 of 140 gastric cancers analyzed (61.4%). Positive expression of COX-2 correlated with the depth of tumor invasion (p = 0.015). However, there was no association between COX-2 expression and tumor stage or status of lymph node or distant metastasis. Furthermore, COX-2 expression was not associated with patient survival (p = 0.816). Positive expression of COX-2 occurred more frequently in intestinal than in diffuse or mixed types of cancer and correlated with tumor differentiation (p < 0.001, p = 0.001, respectively). CONCLUSION: These results suggest that COX-2 may play an important role in the evolution of gastric carcinogenesis and be associated with well-differentiated and intestinal type pathways in gastric carcinogenesis. However, COX-2 expression seems to be less useful for establishing prognosis for gastric cancer.     

Correlation between expression of cyclooxygenase-2 and angiogenesis in human gastric adenocarcinoma

AIM: To evaluate the expression of cyclooxygenase (COX2) and the relationship with tumor angiogenesis and advancement in gastric adenocarcinoma.METHODS: Immunohistochemical stain was used for detecting the expression of COX-2 in 45 resected specimens of gastric adenocarcinoma; the monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and microvascular density (MVD) was detected by counting of CD34-positive vascular endothelial cells. Paracancerous tissues were examined as control.RESULTS: Immunohistological staining with COX-2-specific polyclonal antibody showed cytoplasmic staining in the cancer cells, some atypical hyperplasia and intestinal metaplasia,as well as angiogenic vasculature present within the tumors and prexisting vasculature adjacent to cancer lesions. The rate of expression of COX-2 and MVD index in gastric cancers were significantly increased, compared with those in the paracancerous tissues (77.78 vs 33.33 %, 58.13±19.99 vs 24.02±10.28, P＜0.01, P＜0.05, respectively). In 36 gastric carcinoma specimens with lymph node metastasis, the rate of COX-2 expression and MVD were higher than those in the specimens without metostasis (86.11 vs 44.44 %,58.60±18.24 vs 43.54±15.05, P＜0.05, P＜0.05, respectively).The rate of COX-2 expression and MVD in the specimens with invasive serosa were significantly higher than those in the specimens without invasion to serosa (87.88 vs 50.0 %,57.01±18.79 vs42.35±14.65, P＜0.05, P＜0.05). Moreover,MVD in COX-2-positive specimens was higher than that in COX-2-negative specimens (61.29±14.31 vs 45.38±12.42,P＜0.05). COX-2 expression was positively correlated with MVD (r=0.63, P＜0.05).CONCLUSION: COX-2 expression might correlate with the occurance and advancement of gastric carcinoma and is involved in tumor angiogenesis in gastric carcinoma. It is likely that COX-2 by inducing angiogenesis can be one of mechanisms which promotes invasion and metastasis of gastric carcinoma. It may become a new therapeutic target for anti-angiogenesis.     

Overexpression of cyclooxygenase-2 and tumor angiogenesis in human gastric cancer

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) protein is overexpressed in various cancers, including esophageal, gastric, colon, and pancreatic. To better comprehend the role of COX-2 in gastric cancer, especially with regard to angiogenesis, we investigated COX-2 and vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in 108 patients with gastric cancer. METHODOLOGY: We used immunohistochemical analysis of formalin-fixed tissues of gastric cancer. RESULTS: Expression of COX-2 showed diffuse staining in the cytoplasm of tumor cells, however, no staining in normal epithelial cells. Of the 108 tumors examined, 71 (65%) were positive for COX-2 expression, the VEGF-positive cases numbered 43 of 108 cases (39.8%). The intensity of COX-2 expression did not correlate with any clinicopathological characteristics. The positive rate of VEGF expression in COX-2-positive cases was significantly higher than in COX-2-negative ones (47.9% vs. 24.3%, P<0.05). MVD in COX-2-positive cases was significantly higher than in COX-2-negative ones (22.0+/-7.8 vs. 18.5+/-7.5/1 mm2; P<0.05). CONCLUSIONS: Our study provides evidence that COX-2 is closely related with angiogenesis.     

Eicosanoid regulation of angiogenesis in tumors

Tumor angiogenesis, the formation of new capillary blood vessels in tumors from pre-existing vasculature, is required for tumor growth and progression. Eicosanoids, the bioactive lipids derived from arachidonic acid, possess potent and diverse biological activities. In response to stimuli, arachidonic acid is mobilized from phospholipid pools and metabolized by cyclooxygenases (COX), lipoxygenases (LOX), and p450 epoxygenases (EOX) to form a variety of eicosanoids. The involvement of eicosanoids in tumor angiogenesis and progression is implicated by the observations that nonsteroidal anti-inflammation drugs (NSAIDs) reduce tumor growth and angiogenesis. Subsequently, it is found that the levels of COX-2 and/or 12-LOX are frequently increased in various cancers. Further studies using molecular and pharmacological approaches have found that COX-2 and 12-LOX, when overexpressed in carcinoma cells, enhance their angiogenic potential and stimulate tumor growth. In this article, we discuss how COX and LOX in cancer cells modulate tumor angiogenesis and present the possibility of using NSAIDs and LOX inhibitors as antiangiogenesis agents.     

Helicobacter pylori eradication to prevent gastric cancer： underlying molecular and cellular mechanisms

Numerous cellular and molecular events have been described in development of gastric cancer. In this article, we overviewed roles of Helicobacter pylori (H pylori) infection on some of the important events in gastric car-cinogenesis and discussed whether these cellular and molecular events are reversible after cure of the infection. There are several bacterial components affecting gastric epithelial kinetics and promotion of gastric carci-nogenesis. The bacterium also increases risks of genetic instability and mutations due to NO and other reactive oxygen species. Epigenetic silencing of tumor suppressor genes such as RUNX3 may alter the frequency of phe-notype change of gastric glands to those with intestinal metaplasia. Host factors such as increased expression of growth factors, cytokines and COX-2 have been also reported in non-cancerous tissue in H py/ori-positive subjects. It is noteworthy that most of the above phenomena are reversed after the cure of the infection. However, some of them including overexpression of COX-2 continue to exist and may increase risks for carcinogenesis in metaplastic or dysplastic mucosa even after successful H pylori eradication. Thus, H pylori eradication may not completely abolish the risk for gastric carcinogenesis. Efficiency of the cure of the infection in suppressing gastric cancer depends on the timing and the target population, and warrant further investigation.     

NSAID inhibition of GI cancer growth: clinical implications and molecular mechanisms of action

Epidemiological studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of and mortality from colorectal, gastric, and esophageal cancers. The precise mechanisms by which NSAIDs exert their chemopreventive effects are not fully explained, but likely involve inhibition of cyclo-oxygenase, the enzyme that converts arachidonic acid to prostaglandins. Two isoforms of this enzyme, cyclo-oxygenase 1 (COX-1) and COX-2, have been identified. COX-2 is absent in normal mucosa but is overexpressed in colonic, gastric, and esophageal cancers, as well as their precursor lesions. The inhibition of COX-2 through either pharmacological agents or gene deletion results in suppression of colonic polyp formation. NSAIDs reduce colonic, gastric, and esophageal cancer cell growth, in part, by inducing apoptosis. However, the antineoplastic effects of NSAIDs may be partly independent of their ability to inhibit COX-2. The mechanisms involved in the antineoplastic actions of NSAIDs include inhibition of angiogenesis (essential for delivery of oxygen and nutrients to a growing tumor), induction of apoptosis (which is usually reduced in cancer cells) by stimulation of proapoptotic genes, and direct inhibition of cancer cell growth by blocking signal transduction pathways responsible for cell proliferation.     

Tumor suppression induced by intratumor administration of adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte growth factor,and naive dendritic cells

NK4, a 4-kringle antagonist of hepatocyte growth factor (HGF), is a potent inhibitor of tumor angiogenesis and functions independently of its HGF-antagonistic activity. We have shown previously that in vivo genetic modification of tumors with an adenovirus vector that expresses NK4 (AdNK4) restrains tumor angiogenesis and slows the rate of tumor growth in vivo. In the present study, we investigated the hypothesis that this can be made more efficient by also administering bone marrow-generated dendritic cells (DCs) to the tumor. The data show that the growth of mouse subcutaneous tumors is significantly suppressed by direct administration of DCs into established tumors that had been pretreated with AdNK4 3 days previously. The synergistic antitumor effect produced by the combination therapy of AdNK4 with DCs correlated with the in vivo priming of tumor-specific cytotoxic T lymphocytes. Analysis of mice treated with fluorescence-labeled DCs suggested that DCs injected into the flank tumor could migrate to lymphoid organs in vivo for activation of immune-relevant processes. Knockout mice experiments demonstrated that the tumor regression produced by this combination therapy depends on both major histocompatibility complex (MHC) class I antigen presentation of DCs injected into the tumors and CD8(+) T cells of the treated host. Finally, a mechanism for this synergism was suggested by the histological observation that tumor necrosis and apoptosis were induced by genetic engineering of the tumors to express NK4. These findings should be useful in designing novel strategies that use a combination of 2 monotherapies directed against the vascular and immune systems for cancer therapy.     

Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer

Background Recent studies have reported that expression of monocyte chemoattractant protein 1 (MCP-1) and its receptor (CCR2) and CD40 ligation on mesenchymal cells play important roles in tumor development. Cyclooxygenase 2 (COX-2) has also been shown to contribute to tumor angiogenesis. We examined the interaction between MCP-1 and CD40 ligation in mesenchymal cells in gastric cancer to determine the effect of these factors on vascular endothelial growth factor (VEGF) production via upregulation of COX-2 expression. Methods COX-2, prostaglandin E₂ (PGE₂), and VEGF production were evaluated in CD40 ligand (CD40L)-stimulated macrophages. CD40L and MCP-1 mRNA levels in gastric cancer tissues were evaluated by real-time polymerase chain reaction (PCR). Localizations of MCP-1, CD40L, CD34, CD40, and CCR2 in 34 gastric cancer tissue specimens were evaluated by single-or double-label immunohistochemistry. Results COX-2 expression levels were significantly higher in CD40L-stimulated macrophages and correlated with increased PGE₂ and VEGF production. Addition of MCP-1 to CD40L-stimulated macrophages had a synergistic effect on COX-2 expression and subsequent PGE₂ and VEGF production. CD40L and MCP-1 mRNA levels were significantly higher in poorly differentiated gastric cancers than in H. pylori-infected gastritis patients. High microvessel density was significantly associated with MCP-1 and CCR2 scores and lymph node metastasis. Conclusions MCP-1 and CD40L had a synergistic effect on COX-2 expression and subsequent VEGF production in gastric cancer.     

Genetic variant of cyclooxygenase-2 in gastric cancer: More inflammation and susceptibility

Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5’ and 3’ untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.     

环氧合酶-2和血管内皮生长因子-C与胃癌淋巴管转移

目的　研究环氧合酶 2 (COX 2 )和血管内皮生长因子 (VEGF) C在胃癌组织中的表达及相关性 ,探讨二者在胃癌淋巴管生成和转移中的作用。方法　采用免疫组化方法和逆转录 PCR技术 ,分别检测了 6 4例胃癌石蜡组织中COX 2和VEGF C的表达及其中 2 2例胃癌新鲜组织中二者mRNA的表达。结果　 2 2例胃癌新鲜组织中COX 2和VEGF CmRNA表达阳性率分别为 82 %和73% ,其表达均高于相应的癌旁正常组织 (P <0 0 0 1) ,与 6 4例胃癌石蜡标本COX 2和VEGF C的表达结果较一致。且COX 2和VEGF C表达之间存在明显关联性 (P <0 0 5 )。二者在癌组织中的高表达与肿瘤浸润深度、淋巴结转移等密切相关 (P <0 0 5 )。结论　胃癌组织中有COX 2和VEGF C的高表达 ,而COX 2可能参与VEGF C淋巴管生成通路 ,它们的表达可能在胃癌淋巴管浸润和转移中发挥重要作用     

环氧合酶—2蛋白在胃癌组织中的表达

流行病学调查发现长期使用非巢体类抗炎药（ＮＳＡＩＤｓ）的患者强肠癌发病率明显下降。ＮＳＡＩＤｓ能抑制环氧合酶（ＣＯＸ）,而ＣＯＸ－２在结肠癌的发生、发展中起一定作用。目的：调查ＣＯＸ－２蛋白在胃癌组织中的表达。方法：用免疫组化半定量方法检测ＣＯＸ－２和ＣＯＸ－１蛋白在胃癌及相应正常组织中的表达。结果：９７．１％（３３／３４）的胃癌组织中有ＣＯＸ－２蛋白表达,其强度明显高于正常胃窦粘膜,分伦型胃癌的     

Cyclooxygenase-2 expression and angiogenesis in gastric hyperplastic polyp--association with polyp size

BACKGROUND: Cyclooxygenase (COX)-2 is the rate-limiting enzyme in prostaglandin synthesis, and plays an important role in tumor enlargement. COX-2 is expressed in human gastric and colorectal tumors, and the expression increases in a tumor size-dependent manner. In the present study, we attempted to examine the COX-2 expression pattern in gastric hyperplastic polyp, a non-tumorous lesion. PATIENTS AND METHODS: Fifty-eight gastric hyperplastic polyps, obtained by endoscopic polypectomy, were immunostained with anti-COX-2 and antivascular endothelial growth factor (VEGF) antibodies. Microvessel density (MVD) was determined by von Willebrand factor immunostaining. RESULTS: In larger gastric hyperplastic polyps, COX-2 was expressed mainly on the luminal side of the polyp stroma, while it was absent in smaller polyps. A significant correlation between COX-2 immunoreactivity and polyp size was observed (p < 0.01). High VEGF expression and MVD were observed mainly in the same stromal region of the polyps where COX-2 was expressed. Both VEGF expression and MVD were also correlated with polyp size significantly (ps < 0.01). CONCLUSIONS: COX-2 expression increased in a size-dependent manner in non-tumorous hyperplastic polyps, suggesting that COX-2 expression is not necessarily linked to epithelial cell transformation. Moreover, COX-2 may participate in polyp enlargement through angiogenesis by promoting VEGF production.     

Anti-cancer effects of COX-2 inhibitors and their correlation with angiogenesis and invasion in gastric cancer

AIM: To observe the anti-cancer effects of COX-2 inhibitors and investigate the relationship between COX-2 inhibitors and angiogenesis, infiltration or metastasis in SGC7901 cancer xenografts. METHODS: Thirty athymic mice xenograft models with human stomach cancer cell SGC7901 were established and divided randomly into 3 groups of 10 each. Sulindac, one non-specific COX inhibitor belonging to non-steroidal anti-inflammatory drugs (a series of COX inhibitors known as NSAIDs) and celecoxib, one selective COX-2 inhibitor (known as SCIs) were orally administered to mice of treatment groups. Immunohistochemistry was used to examine the expression of PCNA, CD44v6 and microvessel density (MVD). Apoptosis was detected by using TUNEL assay. RESULTS: Tumors in sulindac and celecoxib groups were significantly smaller than those in control group from the second week after drug administration (P<0.01). In treatment group, the cell proliferation index was lower (P<0.05) and apoptosis index was higher (P<0.05) than those in control groups. Compared with the controls, microvessel density was reduced (P<0.01) and expression of CD44v6 on tumor cells was weakened (P<0.05) in treatment groups. CONCLUSION: COX-2 inhibitors have anticancer effects on gastric cancer. They play important roles in angiogenesis and infiltration or metastasis of stomach carcinoma. The anticancer effects of COX-2 inhibitors may include inducing apoptosis, suppressing proliferation, reducing angiogenesis and weakening invasiveness.     

环氧化酶-2与肺癌

环氧化酶-2（COX-2）在肺癌细胞呈过表达,并且促进肿瘤增殖、侵袭、血管生成和抗凋亡。COX-2抑制剂在动物实验中可抑制肿瘤生长。进一步了解COX-2介导的肿瘤生成及其与其它分子的相互作用机制可能为肺癌的治疗提供新的途径。     

Non-steroidal anti-inflammatory drugs in prevention of gastric cancer

Non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase 2 (COX-2) selective inhibitors, are potential agents for the chemoprevention of gastric cancer. Epidemiological and experimental studies have shown that NSAID use is associated with a reduced risk of gastric cancer although many questions remain unanswered such as the optimal dose and duration of treatment. The possible mechanisms for the suppressor effect of NSAIDs on carcinogenesis are the ability to induce apoptosis in epithelial cells and regulation of angiogenesis. Both COX-dependent and COX independent pathways have a role in the biological activity of NSAIDs. Knowledge of how NSAIDs prevent neoplastic growth will greatly aid the design of better chemopreventive drugs and novel treatments for gastric cancer.