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<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 betweenPTEN 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 gaslyic 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 (y = 0.512, P<0.05). VEGF expression in PTEN-negative gaslyic 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. 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.     

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.     

Expression of PTEN and its correlation with angiogenesis in gastric carcinoma]

BACKGROUND/AIMS: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a recently clarified tumor suppressor gene located in 10q23.3. Alterations of this gene are associated with tumor progression and unfavorable outcome in various human cancers. Recently, PTEN has a possible role in angiogenesis by modulating angiogenic factor including vascular endothelial growth factor (VEGF). The aim of this study was to investigate the roles of PTEN and VEGF status for angiogenesis in human gastric cancer. METHODS: We conducted an immunohistochemical investigation of PTEN and VEGF expression in 90 cases of paraffin section obtained from gastric cancer patients undergone surgical treatment. RESULTS: Negative expression of PTEN and positive expression of VEGF in gastric cancer tissues, were demonstrated in 40.0% and 77.8% of cases, respectively. However, no significant correlation was found between PTEN, VEGF expression and various clinicopathological parameters. PTEN expression did not correlate significantly with VEGF expression (p=0.301). High microvessel density (MVD) was significantly associated with lymph node metastasis and poor survival (p=0.014, 0.011, respectively). The mean MVD value of PTEN negative tumors was 90.4+/-43.0 and significantly higher than that of PTEN positive tumors (p=0.028). The mean MVD value of VEGF positive tumors was 86.4+/-6.7 and significantly higher than that of VEGF negative tumors (p=0.002). The mean MVD value of PTEN negative and VEGF positive tumors was 98.0+/-42.2, and significantly higher than those of the others. CONCLUSIONS: These results suggest that loss of PTEN expression may play a critical role in tumor progression and metastasis by stimulating tumor angiogenesis in human gastric cancer.     

Relationship between the expression of iNOS, VEGF, tumor angiogenesis and gastric cancer

AIM: To investigate the relationship between theexpression of inducible nitric oxide synthase(iNOS),vascular endothelial growth factor(VEGF),themicrovascular density(MVD) and the pathologicalfeatures and clinical staging of gastric cancerMETHODS: Immunohistochemical staining was used fordetecting the expression of iNOS and VEGF in 46resected specimens of gastric carcinoma; themonoclonal antibody against CD34 was used fordisplaying vascular endothelial cells, and MVD wasdetected by counting of CD34-positive vascularendothelial cells.RESULTS: Of 46 resected specimens of gastriccarcinoma,the rates of expressions of iNOS and VEGFwere 58.70% and 76.09%, respectively,and MVDaveraged 55.59± 19.39.Judged by the standard TNMcriteria, the rate of expression of iNOS in stage ⅣV(84.46%) was higher than those in stage Ⅰ, Ⅱ, Ⅲ(Fishexact probabilities test, P=0.019,0.023 and 0.033,respectively);the rates of expression of VEGF in stageⅢ, Ⅳ (76.0%,92.31%, respectively) were higher thanthose in stage Ⅰ, Ⅱ (Fish exact probabilities test,P=0.031,0.017,0.022 and 0.019). MVDs in stage Ⅲ, Ⅳ(64.72 ± 14.96,67.09± 18.29,respectively) werehigher than those in stage Ⅰ ,Ⅱ(t=2.378,4.015,2.503and 2.450,P＜0.05,P＜0.001,P＜0.001,P＜0.05,respectively). In 37 gastric carcinoma specimens withlymph node metastasis, MVD(68.69±18.07) and therates of expression of iNOS and VEGF(70.27%,83.78%,respectively) were higher than those in the specimenswith absence of metastasis (t=2.205, x2=6.3587,x2=6.2584,P＜0.01, P＜0.05,P＜0.05, respectively). MVDand the expressions of iNOS and VEGF were notcorrelated to the location ,size or grade of tumor, nor withthe depth of invasion of tumor; MVDs in the positive iNOSand VEGF specimens(59.88±18.02,58.39±17.73,respectively) were higher than those in the negative iNOSand VEGF specimens (x2=6.3587 and 6.1574, P＜0.05,P＜0.05,respectively) ;thus the expressions of iNOS andVEGF was correlated to MVD, but the expression of iNOSwas not correlated to that of VEGF. In addition,of the46 surviving patients, the 5-year survival rate ofpatients with positive iNOS or VEGF tumors wassignificantly less than that of patients with negativeiNOS-or VEGF tumors(x2=4.3842 and 5.4073,P＜0.05,P＜ 0.05,respectively).CONCLUSION: The expressions of iNOS and VEGF areclosely related to tumor angiogenesis, and are involvedin the advancement and the lymph node metastasis;thus MVD and the expressions of iNOS and VEGF mayserve indexes for evaluating staging of gastriccarcinoma and forecasting its risk of metastasis, whichwill help establish a comprehensive therapeuticalmeasure of post-operative patients and provide a newapproach to tumor therapy.     

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。     

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 β3 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 β3 mRNA in non-tumor gastric mucosa （20%） was significantly lower than that of the gastric cancer tissue （52.5%, X^2 = 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）,     

Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer

To clarify whether and how PTEN and the phosphatidylinositol 3-kinase/Akt pathway relates to endometrial cancer we examined the expression of these pathway-related proteins in patients with endometrial cancer. Of 103 endometrial cancers, 37 (36%) showed negative immunohistochemical staining for PTEN. Western blotting revealed that the level of phosphorylated Akt expression in PTEN-negative cases was significantly higher compared with that in positive cases. We found a significant inverse correlation between PTEN and phosphorylated Akt. The present study indicates the phosphorylation of Akt accompanied by the loss of PTEN in clinical specimens of endometrial cancers. In order to investigate the relationship between PTEN expression and prognosis in endometrial cancer, 98 patients with advanced endometrial cancer were newly enrolled. The survival rate for PTEN-positive patients was significantly higher than that for PTEN-negative or -heterogeneous staining patients. Of the 98 patients, 25 underwent radiation therapy, 62 received chemotherapy after surgery, and the remaining 11 did not have any postoperative treatment. When patients underwent chemotherapy, the survival rate for PTEN-positive cases was clearly higher than that for PTEN-negative or -heterogeneous cases (62.4 vs 11.8%). Subsequent multivariate analysis revealed that PTEN staining was an independent prognostic factor for patients undergoing chemotherapy. The current study demonstrates that PTEN-positive staining is a significant prognostic indicator of favorable survival for patients with advanced endometrial cancer who undergo postoperative chemotherapy.     

Galectin-1在胃癌组织中的表达及在胃癌血管生成中的作用

目的研究半乳糖凝集素1（Gal-1）在胃癌组织中的表达,并分析其与肿瘤血管生成的关系。方法采用实时荧光定量RT-PCR技术从mRNA水平检测胃癌组织及远癌切端胃组织中Gal-1的表达情况,并用免疫组织化学SABC法检测各标本中Gal-1蛋白、血管内皮生长因子（VEGF）表达及其微血管密度（MVD）。分析Gal-1、VEGF与临床病理参数及MVD之间的关系。结果胃癌组织Gal-1 mRNA及蛋白表达、VEGF表达、MVD均分别高于远癌切端胃组织（P均〈0.05）。胃癌组织Gal-1 mRNA及蛋白表达、VEGF表达和MVD与浸润深度、TNM分期及淋巴结转移相关,胃癌组织Gal-1表达与VEGF、MVD呈正相关（P〈0.05）。结论 Gal-1通过促进肿瘤微血管生成参与胃癌的生长和侵袭,可作为诊断及判断胃癌进展程度及预后的指标。     

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。     

通过IFN-γ影响肿瘤相关巨噬细胞抑制胆囊癌血管发生的实验研究

目的研究IFN－γ影响胆囊癌中肿瘤相关巨噬细胞（TAM）促血管发生的能力。方法通过接种人胆囊癌细胞株GBC—SD构建人胆囊癌裸鼠皮下肿瘤模型,给予肿瘤内注射IFN-γ处理,通过免疫组化法计数浸润的单核－巨噬细胞、TAM和微血管密度（MVD）,并计算TAM分化率;通过ELISA法检测肿瘤内小鼠血管内皮生长因子（VEGF）的分泌情况。结果实验组肿瘤中浸润的单核－巨噬细胞高于对照组（P〈0．01）;TAM分化百分率,鼠源性VEGF和MVD均低于对照组（P〈0．05或〈0．01）。结论IFN-γ能够抑制TAM的分化形成,降低胆囊癌中VEGF的浓度,减少胆囊癌的血管发生,从而抑制胆囊癌进展。     

肾上腺皮质肿瘤VEGF、TSP-1的表达及其与微血管密度的关系

目的 研究血管内皮生长因子(VEGF)、血小板反应素1(TSP-1)在肾上腺皮质肿瘤中的表达及其与微血管密度(MVD)的关系.方法 采用免疫组化方法检测13例肾上腺皮质癌、30例肾上腺皮质腺瘤和7例正常肾上腺组织中VEGF、TSP-1及MVD(以CD34为标记)的表达.结果 肾上腺皮质癌VEGF表达高于肾上腺皮质腺瘤,差异有统计学意义(P＜0.01);TSP-1在正常肾上腺皮质表达明显高于肾上腺皮质癌(P＜0.01);MVD在肾上腺皮质癌为(107.67±11.91)/视野,显著高于肾上腺皮质腺瘤(59.46±21.31)/视野和正常肾上腺皮质组织(25.10±3.94)/视野(均P＜0.01);VEGF的表达与MVD呈正相关(P＜0.01),TSP-1的表达与MVD呈负相关(P＜0.01),VEGF与TSP-1的表达呈负相关(P＜0.01).结论 VEGF和TSP-1在肾上腺皮质肿瘤的表达失衡是其肿瘤血管异常生成的重要原因.     

Relationship between the expression of iNOS,VEGF,tumor angiogenesis and gastric cancer

AIM：To in vestigate the relationship between the expression of inducible nitric oxide synthase(iNOS),vascular endothelial growth factor(VEGF),the microvascular density(MVD)and the pathological features and clinical staging of gastric cancer.METHODS:Immunohistochemical staining was used for detecting the expression of iNOS and VEGFin46resected specimens of gastric carcinoma;the monoclonal antibody against CD34 was used for displaying vascular endothelial cells,and MVD was detected by counting of CD34-positive vascular endothelial cells.RESULTS:Of 46resected specimens of gastric carcinoma,the rates of expressions of iNOS and VEGF were 58.70%and76.09%,respectively,and MVDaveraged55.59&#177;19.39,Judged by the standard TNM criteria,the rate of expression of iNOS in stageⅣ（84.46%)was higher than those in stageⅠ,Ⅱ,Ⅲ（Fish exact probabilities test,P=0.019,0.023and 0.033,respectively);the rates of expression of VEGFin stage Ⅲ,Ⅳ（76.0%,92.31%,respectively)were higher than those in stageⅠ,Ⅱ（Fis exact probabilities test,P=0.031,0.017,0.022and0.019).MVDs in stageⅢ,Ⅳ（64.72&#177;14.96,67.09&#177;18.29,respectively)were higher than those in stageⅠ,Ⅱ(t\2.378,4.015,2.503and2.450,P&lt;0.05,P&lt;0.001,P&lt;0.001,P&lt;0.05,respectively),In37gastric carcinoma specimens with lymph node metastasis,MVD(68.69&#177;18.07)and the rates of expression of iNOS and VEGF(70.27%,83.78%,respectively)were higher than those in the specimens with absence of metastasis(t=2.205,X^2=6.3587,X^2=6.2584,P&lt;0.01,P&lt;0.05,P&lt;0.05,respectively),MVD and the expressions of iNOS and EGF were not correlated to the location,size or grade of tumor,nor with the depth of invasion of tumor;MVDs in the positive iNOS and VEGF specimens(59.88&#177;18.02,58.39&#177;17.73,repectively)were higher than those in the negative iNOS and VEGF specimens(X^2=6.3587and 6.1574,P&lt;0.05,P&lt;0.05,respectively);thus the expressions of iNOS and VEGF was correlated to MVD,but the expression of iNOS was not correlated to that of VEGF,In addition.of the 46 surviving patients,the 5-year survival rate of patients with positive iNOS or VEGF tumors was significantly less than that of patients with negative iNOS-or VEGF tumors(X^2=4.3842and 5.4073,P&lt;0.05,P&lt;0.05.respectively).CONCLUSION:The expressions of iNOS and VEGF are colosely related to tumor angiogenesis,and are involved in the advancement and the lymph node metastasis;thusMVD and the expressions of iNOS and EGF may serve indexes for evaluating staging of gastric carcinoma and forecasting its risk of metastasis,which will help establish a comprehensive therapeutical measure of post-operative patients and provide a new approach to tumor therapy.     

胃癌树突状细胞浸润的临床意义及与肿瘤血管生成的相关性

目的:探讨树突状细胞(dendritic cells,DCs)浸润对胃癌生物学行为的影响,并探讨DCs浸润程度与肿瘤血管生成的相关性.方法:采用免疫组织化学染色SP法检测胃原发癌35例及其中淋巴转移癌23例组织中S-100~ DCs的密度,同法检测35例胃原发癌血管内皮生长因子(VEGF)的表达及CD34标记的微血管密度(MVD).结果:随着胃癌浸润程度的增加,间质S-100~ DCs密度的下降,浆膜浸润的胃癌S-100~ DCs密度显著下降,S-100~ DCs与肿瘤浸润深度呈显著负相关(P=0.023);有淋巴转移胃癌S-100~ DCs密度明显低于无淋巴转移者,但无统计学意义;在胃癌转移的淋巴结.随着胃癌转移程度的增加,S-100~ DCs密度显著下降,两者呈显著负相关(r=-0.923,P<0.01);VEGF阳性表达的胃癌S-100~ DCs密度明显低于VEGF阴性表达的胃癌(P=0.157),两者呈负相关(r=-0.128,P=0.464),但均无统计学意义;S-100~ DCs低密度胃癌的MVD显著高于S-100~ DCs高密度胃癌(P=0.013);高MVD胃癌S-100~ DCs密度明显低于低MVD胃癌,胃癌MVD与S-100~ DCs密度呈显著负相关(r= -0.322,P=0.059).结论:胃癌组织的S-100~ DCs浸润程度与胃癌侵袭和淋巴转移密切相关;胃癌DCs浸润程度与肿瘤血管生成的活力密切相关,胃癌细胞释放的VEGF等促血管生成因子可能是肿瘤源性免疫逃逸的重要分子机制之一.     

雷公藤甲素对胶原诱导关节炎大鼠滑膜血管新生的调节作用

目的 观察雷公藤甲素(TP)对血管新生的影响,探讨TP治疗关节炎的作用机制.方法 建立胶原诱导关节炎(CIA)大鼠模型,常规苏木素-伊红(HE)染色,测量关节体积,计算关节炎指数和病理积分,分别检测滑膜和血清中血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(bFGF)和内皮抑素(endostatin)的蛋白表达,并通过CD34给滑膜血管密度计数(MVD).结果 CIA大鼠滑膜和血清中VEGF、bFGF及滑膜MVD明显高于正常组(X2分别为65.3、31.6,q=9.2,三者P＜0.01),endostatin的表达与正常组差异无统计学意义(X2=0.8,P＞0.05).TP治疗后,滑膜和血清中VEGF、bFGF、滑膜MVD均下降(X2分别为19.7、6.0,q=6.5,三者P＜0.01),而endostatin表达却升高(X2=3.9,P＜O.05),甲氨蝶呤(MTX)则主要以endostatin表达升高为主(X2=17.9,P＜0.01).结论 生长因子的表达失衡可能在关节炎的形成及发展过程中起重要作用,TP能够调整生长因子的失衡状态而发挥治疗作用.     

Growth,invasion, metastasis,differentiation, angiogenesis and apoptosis of gastric cancer regulated by expression of PTEN encoding products

AIM: To investigate expression of PTEN in gastric cancer and to explore its roles in tumorigenesis and progression of gastric cancer.METHODS: Formalin-fixed and paraffin-embedded tissues of adjacent non-tumor mucosa and primary foci from 113cases of gastric cancers were studied for the expression of PTEN and Caspase-3 andmicrovessel density (MVD)by streptavidin-peroxidase (S-P) immunohistochemistry with antibodies against PTEN, Caspase-3, and CD34. The relationship between PTEN and Caspase 3 expression and clinicopathological parameters of tumors was compared.RESULTS: Primary gastric cancer cells expressed PTEN less frequently than adjacent epithelial cells of primary foci (54.9％ vs89.4％; P=0.000, χ2=33.474). PTEN expression was significantly associated with invasive depth (P=0.003,rs=0.274), metastasis (P=0.036, rs=0.197), growth pattern (P=0.008, rs=0.282), Lauren′s classification (P=0.000,rs=0.345), and histological classification (P=0.005, rs=0.262)of tumors, but not with tumor size (P=0.639, rs=0.045),Borrmann′s classification (P=0.544, rs=0.070) or TNM staging (P=0.172, rs=0.129). PTEN expression was negatively correlated with MDV in primary gastric cancer (P=0.020,F=5.558). Primary gastric cancer cells showed less frequent immunoreactivity to Caspase-3 than adjacent epithelial cells of primary foci (32.7 ％ vs 50.4 ％; P=0.007,χ2=7.286).Caspase-3 expression was dependent of PTEN expression in primary gastric cancer cells (P=0.000, χ2=15.266).CONCLUSION: Down-regulated expression of PTEN plays an important role in tumorigenesis, progression, growth,differentiation and angiogenesis of gastric cancer. Low expression of PTEN can decrease expression of Caspase-3to disorder apoptosis of tumor cells, which might explain the molecular mechanisms of PTEN contributions to tumorigenesis and progression of gastric cancer.     

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…     

Relationship between expression of CD105 and growth factors in malignant tumors of gastrointestinal tract and its significance

AIM: Angiogenesis is an important step in the growth of solid malignant tumors. A number of angiogenic factors have been found such as transforming growth factorβ1 (TGF-β1)and vascular endothelial growth factor (VEGF). However,the roles of TGFβ1 and VEGF in gastrointestinal carcinogenesis are still unclear. This study was to investigate the expressions of TGF-β1 and VEGF in gastrointestinal tract malignant tumors, as well as their association with microvessel density (MVD). At the same time, we also observed the localization of TGF-β1 and its receptor CD105 in gastric malignant tumors.METHODS: The expressions of TGF-β1 and CDL05 were detected in 55 fresh specimens of gastric carcinoma and VEGF and CD105 in 44 fresh specimens of colorectal carcinoma by immunohistochemical staining (S-ABC). TGF-β1 and CD105 in 55 gastric carcinoma tissues on the same slide were detected by using double-stain Tmmunohistochemistry (DS-ABC).RESULTS: Among the 55 cases of gastric carcinoma tissues,30 were positive for TGF-β1 (54.55 %). The MVD of TGF-β1 strong positive group (++～+++ 23.22±5.8) was significantly higher than that of weak positive group (+17.56±7.2) and negative group (- 17.46±3.9) (q=4.5, q=5.3207, respectively,P＜0.01). In the areas of high expression of TGF-β1, MVD and the expression of CD105 were also high. Among the 44 cases of colonic carcinoma tissues, 26 were positive for VEGF (59.1%). The expressions of both VEGF and CD105 (MVD)were related with the depth of invasion (F=5.438, P＜0.05;F=4.168, P=0.05), lymph node metastasis (F=10.311, P＜0.01;F=20.282, P＜0.01) and Dukes stage (F=6.196, P＜0.01;F=10.274, P＜0.01), but not with histological grade (F=0.487,P＞0.05). There was a significant correlation between the expression of VEGF and CD105 (MVD) (r=0.720, P＜0.01).CONCLUSION: Over-expression of TGF-β1 and VEGF acts as stimulating factors of angiogenesis in gastrointestinal tumors.CD105, as a receptor of TGF-β1, can regulate the biological effect of TGF-β1 in tumor angiogenesis. MVD marked by CD105 is more suitable for detecting newborn blood vessels.     

COX-2 expression in gastric cancer and its relationship with angiogenesis using tissue microarray

AIM： To explore the expression and clinicopathological significance of cyclooxygenase-2 （COX-2） and microvessel density （MVD） in gastric carcinogenesis, and to investigate their roles in the invasion and the relationship between biological behaviors and prognosis of gastric cancer.
METHODS： Using Envision immunohistochemistry, COX-2 and CD34 expressions in gastric cancer tissue array were examined. MVD was counted and the relationship between the biological behaviors and prognosis was analyzed.
RESULTS： The expression of COX-2 in gastric cancer tissue was significantly higher than that in normal mucosa （χ^2 = 12.191, P 〈 0.05）. The over-expression of COX-2 in gastric cancer was obviously related to metastasis and depth of invasion （χ^2 = 6.315, P 〈 0.05）, but not related to the histological type and Borrmann type （χ^2 = 5.391 and χ^2= 2.228, respectively）. Moreover, MVD in gastric cancer tissues was significantly higher than that in the normal mucosa （65.49 ± 20.64 vs 36.21 ± 18.47, t/F = 7.53, P 〈 0. 05）. MVD was related to the histologic type and metastasis （t/F= 3.68 and t/F = 4.214, respectively, P 〈 0. 05）, but not related to the depth of invasion and Borrmann type （t/F = 0.583 and t/F = 0.459, respectively）. MVD in COX-2-positive tissues was markedly higher compared to COX-2-negative tissues, indicating a positive correlation between COX-2 expression and MVD （t = 13.12, P 〈 0. 05）.
CONCLUSION： Tissue microarray （TMA） is a powerful tool for rapid identification of the molecular alterations in gastric cancer. COX-2 expression, via inducingangiogenesis, may play an important role in gastric carcinogenesis. It could be served as a determinant factor for clinical prognosis and curative effect.