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…     

Characteristics of familial juvenile polyps expressing cyclooxygenase-2

OBJECTIVES: Familial juvenile polyposis (FJP) is a dominant genetic disorder characterized by colorectal, gastric, and small bowel juvenile polyps, and high risk for gastrointestinal cancer. Patients are treated by repeated endoscopic polypectomies and elective surgery. We determined the characteristics of FJP polyps expressing cyclooxygenase-2 (COX-2). METHODS: A total of 115 colorectal and 6 gastric polyps were available from 17 FJP patients. Comparison tissues were 18 sporadic juvenile colorectal polyps, 6 gastric hyperplastic polyps, 9 normal colons, and 3 colorectal cancers (CRCs). Histology sections were classified and stained for COX-2. The polyps' epithelium and stroma and comparison tissues were quantified for COX-2 by: area of staining (0-3) x intensity (0-3). Epithelial and stromal scores (0-9) and total scores (0-18) were evaluated in relationship to patient's age, polyp site, size, dysplasia, and stromal cellularity. RESULTS: Colonic FJP polyps mean total COX-2 score was 10.3 +/- 6.0, and that of sporadic juvenile polyps 3.6 +/- 2.2 (p < 0.01), and in contrast to the latter, FJP COX-2 scores increased significantly (p < 0.01) with polyp size. Linear regression analysis showed significant associations of COX-2 in FJP polyps with dysplasia (p < 0.01), stromal cellularity (p < 0.01), size (> or =1.5 cm) (p= 0.02), and site (right colon) (p= 0.01), and not with age. COX-2 total scores of gastric FJP polyps and hyperplastic polyps were similar. CONCLUSIONS: Expression of COX-2 in FJP polyps and its association with size and dysplasia suggest that, in these patients, chemoprevention with selective COX-2 inhibitors might be a useful adjunct therapy to colonoscopic polypectomy.     

Comparison of cyclo-oxygenase 2 expression in colorectal serrated adenomas to expression in tubular adenomas and hyperplastic polyps

BACKGROUND AND AIMS: Serrated adenoma (SA) is a newly defined category of colorectal neoplasia that contains features of both adenoma and hyperplastic polyp, and has two patterns, hyperplastic and cerebriform patterns. Since cyclooxygenase 2 (COX-2) has been found upregulated in colorectal cancers and adenomas, we examined whether either the hyperplastic or cerebriform pattern of SA has the potential for tumor progression and should be a target for clinical treatment. PATIENTS AND METHODS: An immunohistochemical scoring system was used to compare COX-2 expression in colorectal SAs (n=79), tubular adenomas (n=66), and hyperplastic polyps (n=21). RESULTS: COX-2 scores were significantly higher in SA of the cerebriform pattern (n=44) than in SA of the hyperplastic pattern (n=35). There was no difference in COX-2 scores between SA of the cerebriform pattern and tubular adenoma. In SA accompanied by hyperplastic polyp (n=26) the hyperplastic components expressed little COX-2, the same as traditional hyperplastic polyps. COX-2 expression in the SA component was similar to that in pure SA. CONCLUSION: SA of the cerebriform pattern should be treated similarly as traditional tubular adenomas. COX-2 induction may additionally be involved in progression from hyperplastic polyp to SA.     

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.     

不同类型胃息肉及胃癌中环氧化酶-2和P16蛋白的表达及相关性

目的:研究不同类型胃息肉及胃癌中COX-2(环氧化酶-2)和P16蛋白的表达,探讨COX-2、P16蛋白在胃癌发生、发展中的作用及其相互关系.方法:采用S-P免疫组织化学方法检测10例正常胃黏膜,30例非肿瘤性胃息肉(炎性及增生性胃息肉),20例肿瘤性胃息肉(腺瘤性胃息肉)和40例胃癌组织中,COX-2和P16蛋白的表达情况.结果:COX-2表达,在正常胃黏膜、非肿瘤性胃息肉、肿瘤性胃息肉及胃癌中分别为10%,13.33%,45%,75%,胃癌组阳性率与其他三组差异有显著性(P<0.05);P16蛋白表达,在正常胃黏膜、非肿瘤性胃息肉、肿瘤性胃息肉及胃癌中分别为90%,86.67%,60%,32.5%,胃癌组阳性率与其他三组差异有显著性(P<0.05).COX-2、P16蛋白表达与胃癌分化程度、淋巴结转移、呈一定相关性.COX-2与P16蛋白的表达呈负性相关(P<0.05).结论:COX-2、P16蛋白在胃癌发生、发展中起一定作用,可作为判定胃癌生物学行为的有用指标.     

The relationship between cyclooxygenase-2 expression and characteristics of malignant transformation in human colorectal adenomas

BACKGROUND AND AIMS: Cyclooxygenase 2 (COX-2) is a target of aspirin and other non-steroidal anti-inflammatory drugs and is implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the extent of COX-2 in pre-malignant colorectal polyps and to assess the relationship between COX-2 and the level of dysplasia in these lesions. METHODS: Whole polypectomy specimens were retrieved from 123 patients by endoscopic or surgical resection. Following formalin fixation and paraffin embedding, the polyps were evaluated histologically for size, type and grade of dysplasia. The extent of COX-2 expression was measured by the avidin-biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to percentage epithelial COX-2 expression. RESULTS: The polyps were of the following histological types: 10 hyperplastic, 35 tubular adenomas, 61 tubulovillous adenomas and 17 villous adenomas. Twenty showed mild dysplasia, 65 moderate dysplasia, and 28 focal or severe dysplasia (including eight with focal invasion). The average polyp size was 1.7 cm. Nine hyperplastic polyps were COX-2-negative and one was COX-2-positive. COX-2 expression was more extensive in larger polyps and in polyps with a higher villous component. There was a significant increase in the extent of COX-2 protein with increasing severity of dysplasia. Within a polyp, there was a focal corresponding increase in COX-2 expression within epithelium showing a higher grade of dysplasia. CONCLUSIONS: COX-2 expression is related directly to colorectal adenomatous polyp size, type and grade of dysplasia. This suggests that the role of COX-2 in colorectal cancer may be at an early stage in the adenoma-to-carcinoma sequence and supports the suggestion that inhibition of COX-2 may be useful chemoprevention for this disease.     

阿司匹林对人胃癌细胞株的作用及机制探讨

目的 观察阿司匹林对人胃癌细胞株SGC7901生长及人胃癌裸鼠移植瘤生长的作用,并初步探讨其作用机制。方法 采用MTT法及流式细胞术检测不同浓度阿司匹林对胃癌细胞增殖及细胞周期的影响;Westem blot法检测阿司匹林对胃癌细胞COX-2、VEGF表达的影响;建立人胃癌裸鼠移植瘤模型,给予阿司匹林20天,观察肿瘤大小,免疫组化检测阿司匹林对肿瘤组织中COX-2、VEGF表达及MVD的影响。结果 阿司匹林对胃癌细胞的增殖具有抑制作用,且呈一定的时间、剂量依赖性;细胞周期分析表明阿司匹枳主要使细胞阻滞在G0/G1期;western blot检测表明阿司匹林能降低胃癌细胞COX-2、VEGF蛋白的表达;阿司匹林对裸鼠移植瘤的生长有抑制作用,免疫组化显示阿司匹林能降低移植瘤组织中(COX-2、VEGF的表达及MVD。结论 阿司匹林对胃癌细胞及裸鼠移植瘤均具有一定的抑制作用,其机制可能是通过对COX-2和VEGF等血管生成相关因子的抑制起作用。     

胃、肠息肉中VEGF、KDR及MVD的表达及相关性

目的探讨胃、肠息肉中血管内皮生成因子(VEGF)、激酶插入嵌合受体/胎肝激酶-1(KDR)、微血管密度(MVD)的表达及相关性。方法采用免疫组织化学方法检测VEGF及KDR在胃、肠息肉组织中的表达水平,计数微血管密度(MVD)。结果胃、肠息肉组织中VEGF、KDR及MVD的表达显著低于胃、肠癌(P0.05),显著高于正常胃、肠黏膜(P0.05),且胃、肠息肉中VEGF、KDR的表达呈正相关(P0.01);直径2.0 cm息肉中VEGF、KDR的表达显著高于直径1.0 cm者,且在年龄50岁患者中表达增高;肠息肉中VEGF、KDR在绒毛状腺瘤、表面呈分叶状者中表达量高,差异有统计学意义(P0.05);肠息肉中VEGF、KDR的表达显著高于胃息肉(P0.01)。结论直径2.0 cm、年龄50岁的患者癌变概率高,肠息肉中腺瘤性息肉、分叶状息肉癌变率高;肠息肉癌变率高于胃息肉,VEGF、KDR、MVD及其相互作用对促进息肉血管生成及癌变的过程可能起到重要作用。     

Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma

AIM: To investigate the role of cyclooxygenase-2(COX-2) and vascular endothelial growth factor (VEGF) in the development of gastric carcinoma and correlation between expression of COX-2 and VEGF and clinicopathologic features in tissues from patients with gastric carcinoma. METHODS: 281 patients with gastric carcinoma who underwent surgical resection between 1990 and 1999 at the First Affiliated Hospital, Anhui Medical University, PRC, were followed up. Expression of COX-2 and VEGF was investigated retrospectively in 232 gastric carcinoma tissues and 60 noncancerous specimens by using immunohistochemistry. RESULTS: The 5-year survival rates of early gastric carcinoma (EGC) and advanced gastric carcinoma (AGC) were 93.4 % and 59.0 %, respectively. Survival time was highly correlated with lymph node metastasis, vascular invasion, depth of invasion and treatment with chemotherapy. Compared with paired noncancerous tissues, expression of COX-2 and VEGF and microvessel density (MVD) value in carcinoma tissue were significantly higher. The MVD value was much higher in COX-2-positive group and VEGF-positive group than that in COX-2-negative group and VEGF-negative group. Expression of COX-2 and VEGF, as well as MVD value were highly correlated with lymph node metastasis and vascular invasion. The 5-year survival rate of patients with expression of COX-2 or VEGF was significantly lower than that of patients without COX-2 or VEGF expression. Multivariate analysis revealed that VEGF overexpression, lymph node metastasis, COX-2 overexpression, depth of invasion and vascular invasion were all independent prognostic factors of gastric carcinoma. CONCLUSION: Overexpression of COX-2 and VEGF in patients with gastric carcinoma can enhance the possibility of invasion and metastasis, implicating a poor prognosis. They may serve as the fairly good prognostic factors to indicate biologic behaviors of gastric carcinoma.     

Involvement of cyclooxygenase-2 and vascular endothelial growth factor in vascularization and lymph node metastasis of colorectal cancers with submucosal invasion

BACKGROUND AND AIMS: Although patients with early colorectal cancer invading the submucosa (CRC-sm) may be treated with endoscopic mucosal resection alone, they generally undergo additional surgery because of the risk of lymph node metastasis. The aims of the present study were to examine the roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in tumor vascularization and to investigate whether COX-2 and VEGF expression and tumor vascularity are useful markers for predicting lymph node metastasis in CRC-sm. METHODS: Twenty-seven resected specimens of CRC-sm with lymph node dissection were examined, and expression of COX-2 and VEGF was evaluated immunohistochemically and scored. Microvessel density (MVD) in CRC-sm tissues was estimated using a Macscope system after CD34 immunostaining. The relationships among clinicopathological parameters, COX-2 and VEGF expression, and MVD in CRC-sm tissues were then analyzed. RESULTS: Scores for COX-2, VEGF and MVD were all significantly higher in patients with CRC-sm with lymphatic invasion or lymph node metastasis. COX-2 score (P < 0.0001) and VEGF score (P = 0.035) were significantly correlated with MVD in CRC-sm tissues. In addition, COX-2 score was significantly correlated with VEGF score in the CRC-sm specimens examined. CONCLUSIONS: Both COX-2 and VEGF are involved in tumor vascularization in CRC-sm. COX-2 expression, VEGF expression, and MVD are possible markers for predicting lymph node metastasis in patients with CRC-sm, and use of COX-2 expression may be clinically practical.     

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.     

Survivin、COX-2和VEGF在胃癌中的表达及其与预后的意义

目的研究生存素(Survivin)、环氧合酶-2(COX-2)和血管内皮生长因子(VEGF)在胃癌组织中的表达,探讨它们表达的关系及其与胃癌预后的关系。方法选取淮南东方医院集团总医院1992~2002年10年间行根治性手术治疗,临床、病理和随访资料齐全的胃癌患者65例,应用免疫组化S-P技术,检测Survivin、COX-2和VEGF在胃癌组织中表达。结果早期胃癌的5年生存率为95.2%(20/21),中期胃癌的5年生存率为63.6%(7/11)。中期胃癌组Survivin阳性表达高于早期胃癌组(73.6%vs 66.7%,P<0.05),其VEGF阳性表达和微血管密度(MVD)平均值高于早期胃癌组(P<0.05)。Survivin和COX-2在慢性萎缩性胃炎中的表达明显低于不典型增生者(P<0.05),在癌组织中的表达明显高于非癌组织(P<0.05)。胃癌组中的VEGF阳性表达率和MVD平均值均明显高于非癌组,且与胃癌浸润深度有关(P<0.05)。胃癌中Survivin、VEGF阳性表达的MVD值显著高于Survivin、VEGF阴性表达者(P<0.05);Survivin、COX-2、VEGF及MVD值与胃癌淋巴结转移、血管浸润均密切相关(P<0.05);Survivin、COX-2阳性表达及VEGF阳性表达者5年生存率明显低于阴性或低表达者(P<0.05)。多因素分析显示,淋巴结转移、浸润深度、Survivin表达、VEGF表达均为胃癌独立的预后因素。结论Survivin、COX-2、VEGF与胃癌的生长和浸润转移关系密切,可以作为反映胃癌生物学行为和判断预后的有效指标。     

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.     

Inactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer

AIM: To investigate the expression of PTEN/MMAC1/TEP1 and vascular endothelial growth factor (VEGF), their roles in biologic behavior and angiogenesis and their association in gastric cancer.METHODS: Immunohistochemical staining was used to evaluate the expression of PTEN, VEGF and microvascular density (MVD) on paraffin-embedded sections in 70 patients with primary gastric cancer and 24 patients with chronic superficial gastritis (CSG). Expression of PTEN, VEGF and MVD were compared with clinicopathological features of gastric cancer. The relationship between expression of PTEN, VEGF and MVD as well as the relationship between PTEN and VEGF expression in caner cells were investigated. RESULTS: PTEN expression significantly decreased (t= 3.98, P&lt;0.01) whereas both VEGF expression and MVD significant increased (t = 4.29 and 4.41, respectively, both P&lt;0.01) in gastric cancer group compared with CSG group. PTEN expression was significantly down-regulated (t=1.95, P&lt;0.05) whereas VEGF expression (t = 2.37, P&lt;0.05) and MVD (t= 3.28, P&lt;0.01) was significantly up-regulated in advanced gastric cancer compared with early-stage gastric cancer. PTEN expression in gastric cancer showed a negative association with lymph node metastasis (t= 3.91, P&lt;0.01), invasion depth (t= 1.95, P&lt;0.05) and age (t= 4.69, P&lt;0.01). MVD in PTEN-negative gastric cancer was significantly higher than that in PTEN-positive gastric cancer (t=3.69, P&lt;0.01), and there was a negative correlation betweenPTEN expression and MVD (γ=-0.363, P&lt;0.05). VEGF expression was positively associated with invasion depth (especially with serosa invasion, t = 4.69, P&lt;0.01), lymph node metastasis (t= 2.31, P&lt;0.05) and TNM stage (t= 3.04, P&lt;0.01). MVD in VEGF-positive gaslyic cancer was significantly higher than that in VEGF-negative gastric cancer (t=4.62, P&lt;0.01), and there was a positive correlation between VEGF expression of and MVD (y = 0.512, P&lt;0.05). VEGF expression in PTEN-negative gaslyic cancer was significantly stronger than that in PTEN-positive gastric cancer (t=2.61, P&lt;0.05), and there was a significantly negative correlation between the expression of VEGF and PTEN (γ=-0.403, P&lt;0.05).CONCLUSION: Our results imply that inactivation of PTEN gene and over-expression of VEGF contribute to the neovascularization and progression of gastric cancer. PTEN-related angiogenesis might be attributed to its up-regulation of VEGF expression. PTEN and VEGF could be used as the markers reflecting the biologic behaviors of tumor and viable targets in therapeutic approaches to inhibit angiogenesis of gastric cancers.     

Tnactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer

AIM: To investigate the expression of PTEN/MMAC1/TEP1and vascular endothelial growth factor (VEGF), their roles in biologic behavior and angiogenesis and their association in gastric cancer.METHODS: Immunohistochemical staining was used to evaluate the expression of PTEN, VEGF and microvascular density (MVD) on paraffin-embedded sections in 70 patients with primary gastric cancer and 24 patients with chronic superficial gastritis (CSG). Expression of PTEN, VEGF and MVD were compared with clinicopathological features of gastric cancer. The relationship between expression of PTEN, VEGF and MVD as well as the relationship between PTEN and VEGF expression in caner cells were investigated.RESULTS: PTEN expression significantly decreased (t= 3.98,P＜0.01) whereas both VEGF expression and MVD significant increased (t = 4.29 and 4.41, respectively, both P＜0.01)in gastric cancer group compared with CSG group. PTEN expression was significantly down-regulated (t = 1.95,P＜0.05) whereas VEGF expression (t = 2.37, P＜0.05) and MVD (t = 3.28, P＜0.01) was significantly up-regulated in advanced gastric cancer compared with early-stage gastric cancer. PTEN expression in gastric cancer showed a negative association with lymph node metastasis (t= 3.91, P＜0.01),invasion depth (t= 1.95, P＜0.05) and age (t= 4.69, P＜0.01).MVD in PTEN-negative gastric cancer was significantly higher than that in PTEN-positive gastric cancer (t = 3.69,P＜0.01), and there was a negative correlation between PTEN expression and MVD (γ = -0.363, P＜0.05). VEGF expression was positively associated with invasion depth (especially with serosa invasion, t = 4.69, P＜0.01), lymph node metastasis (t= 2.31, P＜0.05) and TNM stage (t= 3.04,P＜0.01). MVD in VEGF-positive gastric cancer was significantly higher than that in VEGF-negative gastric cancer (t = 4.62,P＜0.01), and there was a positive correlation between VEGF expression of and MVD (γ = 0.512, P＜0.05). VEGF expression in PTEN-negative gastric cancer was significantly stronger than that in PTEN-positive gastric cancer (t = 2.61,P＜0.05), and there was a significantly negative correlation between the expression of VEGF and PTEN (γ = -0.403,P＜0.05).CONCLUSION: Our results imply that inactivation of PTEN gene and over-expression of VEGF contribute to the neovascularization and progression of gastric cancer. PTENrelated angiogenesis might be attributed to its up-regulation of VEGF expression. PTEN and VEGF could be used as the markers reflecting the biologic behaviors of tumor and viable targets in therapeutic approaches to inhibit angiogenesis of gastric cancers.     

VEGF和MVD可作为判断胃癌患者预后和上消化道出血风险的指标

背景:血管内皮生长因子(VEGF)是主要血管生成调控因子之一,与肿瘤血管发生密切相关,微血管密度(MVD)是评价肿瘤血管发生的重要指标。有研究发现VEGF表达和MVD与胃癌患者的上消化道出血(UGIB)风险相关。目的:探讨VEGF和MVD与胃癌患者临床病理特征、预后和UGIB风险的关系。方法:收集60例伴或不伴UGIB胃癌患者的胃癌手术标本石蜡包埋组织,以免疫组化方法检测VEGF表达和MVD(计数CD34阳性血管内皮细胞)。结果:胃癌组织VEGF阳性表达率为51.7%(31/60),MVD均值为35.18±19.72。伴UGIB的胃癌患者VEGF阳性表达率和MVD均值显著高于不伴UGIB者(VEGF:64.5%对37.9%,P<0.05;MVD:42.70±15.50对27.13±20.80,P<0.01)。VEGF表达和MVD均与胃癌T分期和pTNM分期呈正相关(P<0.01),VEGF表达与肿瘤组织分化呈负相关(P<0.05),MVD与N分期呈正相关(P<0.001)。COX多元回归分析显示MVD是影响胃癌患者术后生存时间的危险因素,而VEGF与术后生存时间无关。结论:VEGF表达和MVD与胃癌患者的临床病理进展和UGIB风险相关,MVD为胃癌患者术后生存时间的重要影响因素,两者可共同作为判断胃癌患者预后和UGIB风险的有效指标。     

Inhibitory effect of arsenic trioxide on angiogenesis and expression of vascular endothelial growth factor in gastric cancer

INTRODUCTION Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parastic infections. Since the early 1990s, arsenic trioxide (As2…     

Correlation of integrin β3 mRNA and vascular endothelial growth factor protein expression profiles with the clinicopathological features and prognosis of gastric carcinoma

AIM: To investigate integrin 133 mRNA and vascular endothelial growth factor (VEGF) protein expression in gastric carcinoma, and its correlation with microvascular density, growth-pattern, invasion, metastasis and prognosis. METHODS: In situ hybridization(ISH) of integrin β3 mRNA and immunohistochemistry of VEGF and CD34 protein were performed on samples from 118 patients with gastric cancer. RESULTS: The positive rate of integrin 133 mRNA in non- tumor gastric mucosa (20%) was significantly lower than that of the gastric cancer tissue (52.5%, x2 = 10.20, P ＜ 0.01). In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of integrin β3 mRNA were significantly higher than those in patients of expanding type (P ＜ 0.01), stage T1-T2 (P ＜ 0.01), non-vessel invasion (P ＜ 0.01), without lymphatic metastasis (P ＜ 0.01), without hepatic and peritoneal metastasis (P ＜ 0.01), respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of VEGF protein were significantly higher than those in patients of expanding type (P ＜ 0.01), stage T1-T2 (P ＜ 0.01), non-vessel invasion (P ＜ 0.01), without lymphatic metastasis (P ＜ 0.01), without hepatic and peritoneal metastasis (P ＜ 0.01), respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the mean MVD were significantly higher than those in patients of expanding type (P ＜ 0.01), stage T1-T2 (P ＜ 0.01), non-vessel invasion (P ＜ 0.01), without lymphatic metastasis (P ＜ 0.01), without hepatic and peritoneal metastasis (P ＜ 0.01), respectively. It was found that the positive expression rate of integrin β3 mRNA was positively related to that of VEGF protein (P ＜ 0.01) and MVD (P ＜ 0.05), meanwhile the positive expression rate of VEGF protein was positively related to NVD (P ＜ 0.05). The mean survival period in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥ 54.9/mm2 was significantly shorter than that in patients with negative expression of integrin β3 mRNA (P ＜ 0.05) and VEGF (P ＜ 0.01), and MVD ＜ 54.9/mm2 (P ＜ 0.01). Five-year survival rate in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥ 54.9/mm2 was significantly lower than those with negative expression of integrin β3 mRNA (P ＜ 0.05), VEGF (P ＜ 0.05), and NVD ＜ 54.9/mm2 (P ＜ 0.01). CONCLUSION: Integrin β3 and VEGF expression can synergistically enhance tumor angiogenesis, and may play a crucial role in invasion and metastasis of gastric carcinoma. Therefore, they may be prognostic biomarkers and novel molecular therapeutic targets.     

Relationship between expression and distribution of cyclooxygenase-2 and bcl-2 in human gastric adenocarcinoma

AIM: To explore expression and distribution features of COX-2 and bcl-2 in human gastric adenocarcinoma tissues and to study its biological significance. METHODS: Totally 36 human gastric carcinoma samples were enrolled in this study (cardiac adenocarcinoma 16 cases, distal gastric adenocarcinoma 20 cases). The expressions of COX-2 and bcl-2 in cancerous tissues and corresponding para-cancerous tissues were investigated by immunohistochemistry using COX-2 polyclonal antibody and bcl-2 monoclonal antibody. The normal gastric mucosa tissues were used as control. RESULTS: The expressions of COX-2 and bcl-2 in gastric carcinoma were significantly higher than that in the para-cancerous tissues (77.8% vs 47.2%, P<0.01, 80.56% vs 58.33%, P<0.05). The expression of COX-2 in cardiac adenocarcinoma was remarkably higher than that in the distal gastric carcinoma (93.8% vs 65.0%, P<0.01). The expression of COX-2 was mainly localized in the cytoplasm of tumor cells and partly in the nucleus. There is a transition of the COX-2 cytoplasmic positivity to nucleic in tumor cells with the increase of gastric carcinoma pathological grade. Interstitial macrophages, fibroblasts and vascular endothelial cells also expressed COX-2. The tissues with higher expression of COX-2 also expressed high level of bcl-2 protein. CONCLUSION: Abnormal expression pattern of COX-2 within the tissues of human gastric cancer is correlated with tumor location and lymph node metastasis. COX-2 may regulate expression of apoptosis suppressor gene (bcl-2) through interaction of tumor cells and stromal cells and play an important role in the generation and development of tumors, which will be of great help in developing new methods for antitumor therapy.     

Aberrant P-cadherin expression is an early event in hyperplastic and dysplastic transformation in the colon

BACKGROUND: Colorectal adenomatous and, probably, hyperplastic polyp development requires epithelial remodelling and stratification, with loss of E-cadherin expression implicated in adenoma formation. We have shown that P-cadherin, normally expressed in stratified epithelia and placenta, is aberrantly expressed in disturbed epithelial architecture associated with colitis. AIMS: (i) To investigate the role of P-cadherin in colonic polyp formation. (ii) To ascertain whether expression of P-cadherin is independent of or correlated with expression of its associated proteins--E-cadherin, beta-catenin, and gamma-catenin. (iii) To determine if P-cadherin is functional regarding catenin binding in polyps. METHODS: Expression and localisation of cadherins (E- and P-) and their associated catenins (beta- and gamma-) were determined in aberrant crypt foci (ACF), in polyps with hyperplastic morphology (hyperplastic polyps and serrated adenomas), and in adenomatous polyps by immunohistochemistry, western blotting, and mRNA in situ hybridisation. Assessment of cadherin-catenin binding was evaluated by co-immunoprecipitation. Adenomatous polyposis coli (APC) mutation was assessed in adenomatous polyps. RESULTS: P-cadherin was expressed from ACF through to hyperplastic and adenomatous polyps. Alterations in E-cadherin and catenin expression occurred later, with variant patterns in (i) ACF, (ii) hyperplastic polyps and serrated adenomas, and (iii) adenomatous polyps. P-cadherin present in adenomas was functional with regard to catenin binding, and its expression was independent of APC mutational status. CONCLUSIONS: P-cadherin is aberrantly expressed from the earliest morphologically identifiable stage of colonocyte transformation, prior to changes in E-cadherin, catenin, and APC expression/mutation. P-cadherin expression alone does not predict tissue morphology, and such expression is independent of that of associated cadherins and catenins.