乳腺癌纤溶分子标志物t-PA、u-PA表达的临床研究

目的:检测乳腺癌患者血浆纤溶分子标志物含量、mRNA水平的变化以探索其与肿瘤浸润、播散的关系及临床意义。方法:采用逆转录、实时定量PCR技术检测30例乳腺癌组织中组织型纤溶酶原激活剂(tPA)、尿激酶型纤溶酶原激活剂(uPA)mRNA水平;用ELISA法同步检测患者血浆纤溶分子标志物含量,包括tPA、uPA、尿激酶型纤溶酶原激活剂受体(uPAR)、纤溶酶抗纤溶酶复合物(PAP)等。结果:乳腺癌患者血浆uPA、uPAR、PAP含量均较正常对照明显升高,其中,有周围淋巴结转移、远处脏器转移者uPA升高更为显著。肿瘤细胞uPAmRNA表达增高,在不同临床分期组中有显著差异,而tPAmRNA则减少。雌孕激素受体双阳性组tPAmRNA表达较其他组为高。结论:乳腺癌患者纤溶功能明显亢进,可能是其易播散、浸润的主要原因之一。逆转录实时定量PCR技术,使tPAmRNA、uPAmRNA有望成为临床上乳腺癌病情监测、预后判断及治疗选择的辅助指标。     

尿激酶型纤溶酶原激活物系统在正常子宫内膜和子宫内膜癌中的表达

 尿激酶型纤溶酶原激活物系统包括尿激酶型纤溶原激活物 (Urokinase- type PlasminogenActivators,u PA)尿激酶型纤溶酶原激活物受体(Receptor for u PA,u PAR)、纤溶酶原激活物抑制剂 (Plasminogen Activator Inhibitor,PAI)。它们是体内生理或病理条件下通过降解胞外基质、介导细胞转移的主要酶系。其与肿瘤关系的研究近年来不断深入 ,本文将对尿激酶分子系统介导的肿瘤浸润与转移的机制 ,其在正常子宫内膜和子宫内膜癌中的表达等方面的进展作一综述。     

尿激酶型纤溶酶原激活因子及抑制剂表达与人大肠癌细胞转移能力的关系

目的　探讨尿激酶型纤溶酶原激活因子 ( u PA)、尿激酶型纤溶酶原激活因子受体 ( u PAR)和纤溶酶原抑制剂 1( PAI- 1)的表达与人大肠癌细胞系转移能力的关系。方法　用 EL ISA方法测定 3个人大肠癌细胞系培养上清液中 u PA、u PAR和 PAI- 1含量 ;用免疫组化 ABC方法检测 u PA、u PAR和 PAI- 1在细胞中的表达 ;分析其表达与大肠癌细胞转移能力的关系。结果　在培养上清液中具有高转移能力的 HT- 2 9d细胞的 u PA、u PAR及 PAI- 1含量明显高于低转移的 HT- 2 9和不转移的 Wi Dr细胞 ,而 HT- 2 9细胞的 u PA、u PAR及 PAI- 1含量则高于 Wi Dr细胞。免疫组化显示 u PA和 PAI- 1在 HT- 2 9d细胞中的表达高于 HT- 2 9和 Wi Dr细胞。结论　 u PA、u PAR和 PAI-1的表达与大肠癌细胞的转移能力密切相关。     

纤溶酶原激活剂在胃癌组织中的含量及其意义

纤溶酶原激活剂在胃癌组织中的含量及其意义许国强，黄怀德，朱志建，彭清壁，王开明纤溶酶原激活剂（ＰＡｓ）对血管内和细胞外基质的蛋白溶解过程起调节作用；ＰＡｓ分为组织型纤溶酶原激活剂（ｔ－ＰＡ）和尿激酶型纤溶酶原激活剂（ｕ－ＰＡ）。本组通过研究两者在胃癌...     

尿激酶型纤溶酶原激活物系列与肿瘤

恶性实体瘤的侵袭、转移是治疗失败和病人死亡的主要原因 ,阐明肿瘤转移的分子机制对癌症的诊断治疗有着重要的价值。近年来尿激酶型纤溶酶原激活物 ( urokinase- type plasminogen activator,u PA)系列因子在肿瘤中的作用成为人们的研究热点。 u PA系列包括 u PA及其前体 ( pro- u PA)、u PA受体 ( u PA receptor,u PAR)及 u PA抑制因子( plasmimogen activator inhibitors,PAIs)等。它们的主要作用是参与纤溶酶原的激活和细胞外基质的降解 ,是介导肿瘤转移侵袭、转移的主要酶系之一 ,本文就近年来的研究进展作一综述。1　 u PA系…     

uPA作用系统的调控与肿瘤

纤溶酶在体内形成是一个重要而复杂的过程，此过程包括纤溶酶原、激活剂、纤溶酶原激活剂抑制剂以及特异性的受体等。尿激酶型纤溶酶原激活剂（ｕＰＡ）可激活纤溶酶原形成有活性的纤溶酶。在许多模型系统中证明了细胞表面ｕＰＡ激活纤溶酶原在细胞外间质降解、基底膜的破坏等过程中都具有重要的作用，并参与肿瘤细胞浸润和转移的过程。     

uPA-uPAR系统在肿瘤评估与治疗中的研究进展

尿激酶型纤溶酶原激活剂-尿激酶型纤溶酶原激活剂受体(uPA-uPAR)系统是一种细胞外蛋白水解酶系统,该系统可激活纤溶酶,进而引发一系列蛋白水解级联反应,在肿瘤细胞的侵袭与转移中发挥重要作用。这为uPA-uPAR系统各组分成为多种恶性肿瘤的潜在预后生物标志物和治疗靶点提供了可能,本文主要介绍了近年来基于uPA-uPAR系统的恶性肿瘤诊断、治疗及预后评价策略。     

晚期恶性肿瘤患者凝血、抗凝、纤溶状况的初步调查

目的调查晚期恶性肿瘤患者凝血、抗凝及纤溶系统分子标志物的改变情况,初步探讨恶性肿瘤的发生发展与凝血状况间的关系。方法采用酶联免疫吸附双抗体夹心法检测68例晚期恶性肿瘤患者和70名正常人与凝血、抗凝、纤溶系统和内源性抗凝防御活性相关的实验室指标,包括血浆纤维蛋白原(Fbg),血管性血友病因子抗原(vWF∶Ag),凝血酶—抗凝血酶复合物(TAT),组织型纤溶酶原活化剂活性(t-PA∶A),尿激酶型纤溶酶原活化剂活性(u-PA∶A),纤溶酶原活化抑制物-1活性(PAI-1∶A),D-二聚体(D-dimer)。结果晚期恶性肿瘤患者的血浆D-二聚体、纤维蛋白原、组织型纤溶酶原活化剂活性、纤溶酶原活化抑制物-1活性、血管性血友病因子抗原的水平较正常人显著升高(P<0.05)。结论晚期恶性肿瘤患者体内存在凝血、抗凝、纤溶系统的激活及内源性抗凝防御活性的降低,机体呈现高凝状态。     

高水平尿激酶纤维蛋白溶酶原激活剂是胃癌患者新的预后标记物

尿激酶型血浆酶原激活剂(uPA)升高与肿瘤浸润及转移有关,数种实验表明抑制uPA活性可抑制肿瘤 浸润,且uPA选择性地表达于一些人类实验性癌的浸润灶中。为探讨uPA及uPA抑制剂-1(PAI-1)对原发性胃癌患者的无癌生存率的相对预示值,作者使用酶联免疫吸附法检查了160例原发性胃癌癌肿及正常粘膜     

胃癌患者手术前、后血液纤溶系统的动态观察

胃癌患者手术前、后血液纤溶系统的动态观察纪春岩张锑＊刘海鹏朱缓缓＊徐从高＊张茂宏＊李志坚测定了２３例胃癌患者术前、术后第１天及术后第１０天血浆纤溶酶原活性（Ｐｌｇ：Ａ）、血浆纤溶激活活性（ＦＡＡ）、血浆纤溶激活抑制活性（ＦＩＡ）、组织型纤溶酶原...     

CLINICAL STUDY OF T-PA AND U-PA EXPRESSION IN PATIENTS WITH GASTROINTESTINAL CANCER

Objective: To study the changes of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA) expressions and fibrinolysis molecular markers in patients with gastrointestinal cancer in order to elucidate their clinical significance. Methods: The plasma levels of t-PA, u-PA, urokinase-type plasminogen activator receptor (u-PAR) and plasmin anti-plasmin complex (PAP) were measured by ELISA. t-PA and u-PA mRNAs were detected by Real-time RT-PCR. Results: The plasma levels of u-PA, u-PAR and PAP were elevated in gastrointestinal cancer patients, while u-PA was markedly elevated in patients with local infiltration, lymph node involvement or distal metastasis. U-PA mRNA was higher and t-PA was lower in gastrointestinal cancer compared to normal tissue. Conclusion: Hyperfibrinolysis is an important factor related with metastasis potential of gastrointestinal cancer, t-PA may be a character of well differentiated tissue.     

Analysis of fibrinolytic proteins in relation to DNA ploidy in prostate cancer

The tissue concentrations of urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were investigated by an ELISA technique in normal and malignant samples of the prostate from 24 patients undergoing radical prostatectomy for organ-confined prostate cancer. The median concentration of u-PA was significantly higher in cancerous than in normal prostate tissue (p = 0.006). No significant increase of u-PAR, PAI-1 and t-PA was found in cancer tissue in comparison with the benign samples (p > 0.05). Assessment of the relationship between fibrinolytic proteins and DNA ploidy revealed an increased u-PA, u-PAR and PAI-1 in diploid prostate cancer as compared with the normal controls. However, in aneuploid cancer u-PA remained high but u-PAR and PAI-1 were decreased. This led to a higher local concentration of u-PA in aneuploid samples than in normal prostate and in diploid prostate cancer. No alteration of median t-PA was found in benign prostate or in diploid or aneuploid prostate cancer. The altered expression of u-PA, u-PAR and PAI-1 in diploid and aneuploid prostate cancer suggests a possible role of fibrinolytic proteins in the different biologic behavior of tumors, and may be one explanation for the higher metastatic potential of aneuploid tumors. Int. J. Cancer 78:320–325, 1998© 1998 Wiley-Liss, Inc.     

Urokinase system expression in gastric carcinoma: prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens

BACKGROUND: The prognostic relevance of urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR), and plasminogen activator inhibitor 1 (PAI-1) in gastric carcinoma was demonstrated in an independent patient series. To the authors' knowledge,the roles of these activators as predictors of aggressive phenotypes in preoperative biopsies, Helicobacter pylori infection, and intestinal metaplasia have to date not been investigated simultaneously in resected tumors. The objectives of the current study were 1) to demonstrate the prognostic relevance of u-PA, u-PAR, and PAI-1 in an independent series; 2) to evaluate u-PA system expression in preoperative biopsy specimens compared with resected tumors; and 3) to evaluate u-PA system expression in intestinal metaplasias and samples with H. pylori infection. METHODS: In 104 patients with gastric carcinoma (median follow-up, 68 mos), u-PA, u-PAR, and PAI-1 in tumors and metaplasias were evaluated immunohistochemically. Preoperative biopsies were evaluated in a subset of patients. Patients were screened for H. pylori (urease) and tumor cells in bone marrow (u-PAR/CK18). RESULTS: u-PA and PAI-1 were confirmed as independent prognostic parameters, and u-PAR was associated with a trend toward a poor prognosis. u-PA system tumor expression was found to be correlated significantly with u-PAR in disseminated tumor cells and H. pylori-infected tumors, implicating a role of H. pylori in protease induction. There was a significant correlation noted between u-PA system staining between preoperative biopsies and the results in resected tumors. The expression of u-PAR and PAI-1 in intestinal metaplasias was found to be associated significantly with advanced tumor stage (depth of invasion; pathologic tumor status) and lymph node involvement (pathologic lymph node status) and was correlated significantly with u-PA system expression in tumors. CONCLUSIONS: To the author's know the current study is the first to date to demonstrate that u-PA system expression may serve as a predictor of risk in intestinal metaplasias and preoperative biopsies, implicating consequences for neoadjuvant therapy. The independent impact on recurrence and survival and a correlation with u-PAR-expression of minimal residual disease were identified in this independent series.     

Relationship Between Plasminogen Activators and Stomach Carcinoma Stage

The antigen levels of plasminogen activators (PAs), tissue-type PA (t-PA) and urokinase-type PA (u-PA), were measured in extracts from 30 gastric carcinomas and corresponding normal gastric mucosa. The t-PA level was significantly higher in normal mucosa than in cancer tissue, while the u-PA level was significantly higher in cancer tissue. The u-PA level increased with increasing tumor stage, and there was a significant difference between early and advanced cancer. The u-PA level also increased with the degree of nodal involvement, and it was higher in undifferentiated tumors than in well-differentiated ones. It was higher in cases with venous invasion, liver metastasis or peritoneal dissemination than in cases without these features.     

原位杂交检测骨巨细胞瘤u-PA、u-PAR和PAI-2 mRNA的表达及意义

目的 研究骨巨细胞瘤（giant cell tumors of bone,GCT)组织u-PA、u-PAR和PAI－2mRNA的表达与GCT病理分级和复发的关系。方法 用原位杂交技术检测42例GCT组织u-PA和u-PAR和PAI－2 mRNA的表达。结果 （1）u-PA、u-PAR和PAI－2mRNA在GCT组织多核巨细胞（MGC）的阳性率分别为64．3％、71．4％和40．5％;单核基质细胞（MC）的阳性率分别为54．8％、45．2％和9．5％。（2）Ⅱ、Ⅲ级和复发组GCT的MGC u-PA mRNA与MC u-PA、u-PAR mRNA的表达率均明显高于Ⅰ级和无复发组（P均＜0．05）。（3）GCT组织两种细胞间的u-PA mRNA表达、MGC u-PAR与PAI－2 mRNA的表达间、MCu-PA与u-PAR mRNA的表达间均呈正相关;MGC PAI－2mRNA的阳性率明显高于MC的阳性率（P均＜0．05）。结论 u-PA、u-PAR mRNA在GCT组织中的表达,尤其是在MC中的表达,提示肿瘤分化较低和有复发倾向;MC可能是GCT中主要的肿瘤细胞。     

Detection of cathepsin B, cathepsin L, cystatin C, urokinase plasminogen activator and urokinase plasminogen activator receptor in the sera of lung cancer patients

The present study aimed to determine the levels of cathepsin B (cath B), cathepsin L (cath L), cystatin C, urokinase plasminogen activator (u-PA) and urokinase plasminogen activator receptor (u-PAR) in the sera of patients with lung cancer compared to healthy controls using ELISA. Concomitantly, the relationship between the components and clinicopathological prognosis was analyzed. The study included 30 healthy volunteers and 105 lung cancer patients. Blood samples were collected and cath B, cath L, cystatin C, u-PA and u-PAR measurements were made using ELISA. Results showed that the levels of cath B, cath L, cystatin C, u-PA and u-PAR were significantly higher in the patient group compared to the healthy controls. The significance was marked for cath B and mild for u-PAR in correlation with lymph node metastasis. There was no significance for other parameters. Notably, patients with a combination of high cystatin C and high cath B levels had significantly lower survival probability as compared to those with cystatin C(+)/cath B(-) or with cystatin C(-)/cath B(-). Similarly, patients with a combination of high u-PA and u-PAR experienced significantly shorter survival. Furthermore, the univariate analysis revealed that cath B, u-PAR, lymph node metastases, stage and grade were related to survival. However, findings of the multivariate Cox analysis indicated that the sera levels of cath B, u-PAR and lymph node metastases may serve as independent prognostic variables in patients with lung cancer.     

Differential biological significance of tissue-type and urokinase-type plasminogen activator in human breast cancer.

Plasminogen activator (PA) is a serine protease existing in two forms known as tissue-type (t-PA) and urokinase-type (u-PA). To examine whether PA is related to the postoperative clinical course of human breast cancer, total PA activity, t-PA activity, u-PA activity, and immunoreactive t-PA were determined in tissue extracts from 144 breast cancer specimens. The patients were initially divided into four groups according to the postoperative clinical course: Group I (83 patients who are disease-free), Group II (20 patients whose first metastases were found only in bone), Group III (19 patients whose first metastases were found in both bone and lung), and Group IV (22 patients whose first metastases were found only in lung). Total PA activity was significantly lower in Groups, II, III and IV than in Group I. Both t-PA activity and t-PA antigen levels were also significantly lower in Groups II, III and IV than in Group I, while no significant difference was found in u-PA activity among these groups, indicating that low activity of total PA in Groups II, III and IV was due to a decrease in t-PA but not in u-PA. In the multivariate analyses, t-PA activity was found to be an independent prognostic factor for relapse-free survival. When four groups of patients were further analysed in terms of nodal status, both t-PA activity and antigen levels were markedly decreased in the node-negative Group II compared with the node-negative Groups III and IV or with the node-positive Groups II, III and IV. Of additional interest, u-PA activity was significantly higher in node-positive patients than in node-negative patients with any group. The clinico-pathologic analyses of the patients in this series showed that node involvement and lymphatic invasion were more frequently positive in Groups III and IV than in Groups I and II. When 144 breast cancers were categorised in terms of combinations of oestrogen receptor (ER) and progesterone receptor (PgR) status, breast cancers which were positive for both receptors were found to contain the highest t-PA activity and antigen. This study provides provocative evidence suggesting a possible differential significance of t-PA and u-PA expression in human breast cancer.     

凝血和纤维蛋白溶解系统与实体瘤静脉血栓形成及转移的相关研究

 【摘要】　目的　探讨凝血和纤维蛋白溶解系统在实体瘤中的变化，对实体瘤易于并发血栓形成的机制以及实体瘤转移机制进行探讨。方法　ELISA 法检测实体瘤患者血浆组织因子（TF）和组织因子途径抑制物（TFPI）、组织型纤溶酶原活化剂（t-PA）、尿激酶型纤溶酶原活化剂（u-PA）及其抑制物PAI-1的浓度。同时发色底物法检测血浆蛋白C活性（PC：A）。结果　血浆TF、TFPI、u-PA、PAI-1 浓度实体瘤均高于正常对照；发生转移组高于无转移者。死亡组 u-PA、PAI-1高于存活组而TFPI降低。并发静脉血栓组t-PA明显增高而PC：A低于对照组。结论　实体瘤患者容易形成静脉血栓与其存在的凝血系统和纤维蛋白溶解系统紊乱有关；凝血和纤维蛋白溶解相关因子参与了肿瘤的转移和向周围组织的浸润；u-PA、PAI-1及TFPI与肿瘤预后有关。