喉癌组织中尿激酶型纤溶酶原激活剂及其抑制剂的表达及意义

目的：研究尿激酶型纤溶酶原激活荆(urokinase-type plasminogen activator，uPA)和纤溶酶原激活剂抑制剂-1(plasminogen activator inhibitor-1，PAI-1)在喉癌组织中的表达及其临床意义。方法：应用SABC法检测51例声门上型喉癌患者中的uPA与PAI-1的表达，结合临床随访，分析其与临床病理指标的关系及预后的作用。结果：uPA和PAI-1的染色阳性率分别为64．7％(33／51)和70．6％(36／51)。uPA和PAI-1的表达均与临床分期和颈淋巴结状况相关，与肿瘤大小、T分期和病理学分级无关。单因素分析显示，uPA和PAI-1的表达与颈淋巴结转移有相似预后作用；多因素分析显示，uPA和颈淋巴结转移是影响患者预后的独立因子。结论：uPA和PAI-1的表达与喉癌的临床分期和颈淋巴结转移有关，uPA阳性表达者可能预后较差。     

卵巢恶性肿瘤组织中uPA PAI-1蛋白表达与其临床病理因素的关系

目的：最近研究表明尿激酶型纤溶酶原激活因子（urokinase-type plasminogen activator，uPA）及其1型抑制因子（PAI-1）在恶性肿瘤的发生、发展及转移过程中起重要作用，且其过度表达与预后差有关。本研究从蛋白水平探讨uPA及PAI-1表达与卵巢肿瘤发生、发展及预后的关系。方法：采用SABC免疫组织化学方法检测40例卵巢恶性肿瘤（Ⅰ～Ⅱ期14例，Ⅲ～Ⅳ期26例）、20例良性肿瘤及20例正常卵巢组织uPA及PAI-1蛋白的表达。结果：1）uPA、PAI-1在恶性肿瘤中的表达率为52．5％及67．5％，明显高于良性肿瘤及正常组织，差异均有显著性（P〈O．05），而良性肿瘤与正常组织无明显差异（P〉O．05）。2）uPA、PAI-1在恶性卵巢肿瘤中表达与病理类型、腹水多少、有无淋巴结转移无关。3）uPA、PAI-1在Ⅲ～Ⅳ期的表达率明显高于Ⅰ～Ⅱ期，大网膜及肝有转移者明显高于无转移者；uPA表达与肿瘤分化程度呈负相关．PAI-1与残存灶大小呈正相关。4）uPA阴性表达者的平均总生存期（49．0个月）明显高于阳性者（29．3个月）：PAI-1阴性表达者的平均总生存期（52．2个月）明显高于阳性者（31．8个月），（P均〈O．01）。5）COX模型分析显示PAI-1蛋白表达可作为独立的预后指标。结论：uPA、PAI-1与卵巢肿瘤的发生、恶化有关，可作为估计肿瘤转移潜能及预后的重要指标。     

上皮性卵巢癌组织中p21WAF1表达及其与P53和PCNA的相关性

背景与目的:近年研究表明,p21WAF1下调与多种肿瘤发生、发展有关,但其与上皮性卵巢癌的关系研究甚少,本研究从mRNA和蛋白水平探讨p21WAF1基因在上皮性卵巢癌发生发展中的作用及其与P53和PCNA蛋白表达的相关性.方法:应用RT-PCR法检测55例上皮性卵巢癌、32例良性卵巢肿瘤和30例正常卵巢组织中p21WAF1 mRNA表达,免疫组化法检测P21WAF1、P53、PCNA蛋白表达,并结合其临床病理参数及预后进行分析.结果:上皮性卵巢癌、良性卵巢肿瘤、正常卵巢组织中p21WAF1 mRNA阳性率分别为40.00%、56.25%、73.33%(P=0.012),P21WAF1蛋白阳性率分别为36.36%、56.25%、80.00%(P=0.001).上皮性卵巢癌p21WAF1 mRNA及其蛋白表达均低于其它两组,而P53、PCNA蛋白表达阳性率显著高于其它两组(P＜0.05).上皮性卵巢癌中p21WAF1 mRNA表达与其蛋白表达呈显著性正相关,与PCNA表达呈负相关,与P53表达无显著性相关.P21WAF1蛋白表达与PCNA、P53表达均呈负相关.P21WAF1蛋白低表达与卵巢癌FIGO分期晚有显著性相关(P=0.032),与患者年龄、组织学类型、病理分级、残余肿瘤大小无显著性相关(P＞0.05),而p21WAF1 mRNA与上述各项临床病理参数均无显著性相关(P＞0.05).单因素分析显示p21WAF1 mRNA与P21WAF1蛋白低表达患者预后差(P＜0.05).结论:上皮性卵巢癌组织中P21WAF1表达下调.p21WAF1基因检测结果有可能作为预测上皮性卵巢癌预后的一种参考指标.     

尿激酶型纤溶酶原激活物在卵巢上皮性癌组织中的表达与受体及临床预后的关系

 目的 探讨尿激酶型纤溶酶原激活物（uPA）在卵巢上皮性癌中的表达、与受体（uPAR）蛋白表达的相关性以及与临床预后的关系。方法 应用链霉素抗生素蛋白过氧化酶连接（SP）技术，检测68例上皮性卵巢癌组织中uPA、uPAR蛋白的表达水平，并与卵巢上皮性交界性肿瘤、良性卵巢肿瘤及正常卵巢组织各10例进行对照。结果 卵巢上皮性癌组织中，uPA蛋白的表达率为86.76 %，显著高于交界性肿瘤、良性卵巢肿瘤及正常卵巢组织的表达率（50.00 %、40.00 %及20.00 %）（P＜0.05）。uPA蛋白的表达与卵巢上皮性癌的临床分期、组织分级及淋巴结转移有相关性（P＜0.05），与患者年龄、肿瘤大小及病理学类型无相关性（P＞0.05）。uPA蛋白的表达与uPAR的表达呈负相关（P＜0.01）。uPA不同表达强度组间生存时间差异有统计学意义（P＜0.01）。结论 uPA对卵巢上皮性癌的发生和发展起重要的作用。uPA可能与uPAR在卵巢上皮性癌的发展中起拮抗作用。uPA在卵巢癌肿瘤细胞中的表达水平可以作为评估上皮性卵巢癌患者预后的重要指标。     

ADM在上皮性卵巢癌组织中的表达及其临床意义

目的 探讨上皮性卵巢癌中肾上腺髓质素（adrenomedullin,ADM）蛋白的表达及其临床意义.方法 采用免疫组织化学染色,光镜观察结果确定ADM在正常组织及良恶性上皮性卵巢肿瘤组织中的蛋白表达,应用SPSS13.0软件结合临床病理资料进行综合分析.结果 正常组织及良恶性上皮性卵巢肿瘤组织中ADM皆有表达,ADM在卵巢癌组织中的阳性表达率（78.00%,39/50）明显高于正常卵巢组织（10.00%,1/10）及良性卵巢肿瘤组织20.00%（2/10）,具有显著性差异（P＜0.01）;在正常组织和良性卵巢肿瘤组织中的表达无显著性差异（P＞0.05）.ADM表达与病理分级、淋巴结转移及预后明显相关（P＜0.05）,而与年龄、临床分期、组织学类型无关（P＞0.05）.结论 ADM在卵巢癌组织中的表达明显高于正常组织及良性卵巢肿瘤组织,在卵巢癌的浸润和转移中发挥了重要作用,可作为判断卵巢癌恶性程度及评估不良预后的重要指标.     

乳腺癌组织uPA和PAI-1表达与临床病理因素相关性的探讨

目的:探讨尿激酶型纤溶酶原激活物(uPA)、纤溶酶原激活物抑制因子-1(PAI-1)在乳腺癌组织中的表达及其临床意义.方法:免疫组化SP法检测乳腺癌组织及良性乳腺疾病组织中uPA、PAI-1的表达,结合临床病理因素、骨髓微转移状况及随访结果对数据进行统计处理.结果:50例乳腺癌患者癌组织中uPA、PAI-1表达阳性率分别为92.0%和82.0%.与良性乳腺疾病相比,癌组织中两者表达增强,P值均为0.001.癌组织中uPA、PAI-1表达随肿瘤的增大而增高;淋巴结转移阳性者表达强度高;临床分期晚者表达强度高;组织学分级高者表达强度高.ER、PR表达阴性组uPA、PAI-1表达强度较阳性组高,P值均<0.05;c-erbB-2蛋白过表达组uPA、PAI-1表达强度高,P值分别为0.021和0.014; uPA、PAI-1表达强度高者易发生骨髓微转移,且易发生远处转移.uPA与PAI-1的表达呈正相关,r=0.664, P=0.000.结论:乳腺癌组织uPA、PAI-1高表达者发生骨髓微转移及远处转移机会高、预后差,uPA、PAI-1检测可以作为判断乳腺癌预后的指标之一.uPA与PAI-1两者之间存在协同作用.     

ALDH1、ErbB2表达与上皮性卵巢癌组织临床病理特征和预后的关系

目的 探讨上皮性卵巢癌组织中ALDH1、ErbB2表达及与其临床病理特征和预后的关系。方法 选取50例卵巢癌患者,收集患者临床资料,RT-PCR检测组织ALDH1、ErbB2水平,分析其与患者临床病理特征及预后的关系。结果 ALDH1表达与患者年龄、肿瘤最大直径、肿瘤分化程度、淋巴结远处转移情况等无相关性(P>0.05),与FIGO分期有关(P<0.05);ErbB2表达与患者年龄、肿瘤最大直径、肿瘤分化程度等无相关性(P>0.05),与FIGO分期、淋巴结远处转移情况等相关(P<0.05)。单因素分析发现：FIGO分期、淋巴结远处转移、ALDH1、ErbB2表达是影响上皮性卵巢癌预后的因素(P<0.05)。多因素分析显示：FIGO分期、淋巴结远处转移、ALDH1、ErbB2表达是影响上皮性卵巢癌预后的独立危险因素(P<0.05)。结论 上皮性卵巢癌组织中ALDH1、ErbB2表达与其临床病理特征有关,ALDH1、ErbB2表达可作为预测上皮性卵巢癌患者预后的标志物,具有重要的临床意义。     

MiR-126、血管内皮生长因子的表达与微血管密度在上皮性卵巢癌组织中的变化

目的 探讨miR-126、血管内皮生长因子(VEGF)的表达与微血管密度(MVD)在上皮性卵巢癌组织中的变化及意义.方法 采用qRT-PCR检测21例正常卵巢组织、23例良性卵巢肿瘤组织及45例上皮性卵巢癌组织中miR-126表达水平,采用免疫组化法检测VEGF蛋白表达及MVD.结果 MiR-126在上皮性卵巢癌组织中的表达明显低于正常卵巢组织、良性卵巢肿瘤组织(P<0.05);VEGF阳性率和MVD在上皮性卵巢癌组织中明显高于正常卵巢组织、良性卵巢肿瘤组织(P<0.05).上皮性卵巢癌组织中miR-126、VEGF及MVD与FIGO分期、淋巴结转移有关(P<0.05).结论 MiR-126、VEGF可能与上皮性卵巢癌的发生、发展、肿瘤异常血管营养及侵袭转移有关.     

人附睾蛋白4和Lewis y抗原在上皮性卵巢癌组织中的表达及其与化疗耐药和预后的关系

目的:探讨人附睾蛋白4（HE4）与Lewis y抗原在上皮性卵巢癌组织中的表达及其与化疗耐药、患者预后的关系。方法:应用免疫组织化学方法检测HE4和Lewis y抗原在92例上皮性卵巢癌组织（36例化疗耐药,56例化疗敏感）中的表达,分析其与临床病理参数、化疗耐药及预后之间的关系。结果:HE4及Lewis y抗原以胞膜着色为主,卵巢癌耐药组中HE4及Lewis y抗原的高表达率明显高于敏感组（75%,83.3% vs 30.4%,30.4%,P＜0.001）,且二者的表达呈正线性相关(r=0.240,P=0.021),其与临床病理参数未见显著性差异,回归分析发现FIGO分期、HE4及Lewis y抗原的高表达是化疗耐药的独立危险因素(HR:10.230,10.496,10.065,所有P＜0.05),单因素生存分析表明年龄、FIGO分期、残余病灶大小、淋巴转移、化疗是否耐药、Lewis y抗原及HE4的表达都是影响总体生存时间（OS）的重要因素（所有P＜0.05）,Cox多因素生存分析显示FIGO分期和Lewis y抗原是影响OS的独立因素（所有P＜0.05）。结论:HE4与Lewis y抗原在卵巢癌组织中的表达呈正相关性,可以预测卵巢癌的化疗耐药,其高表达提示着患者更差的预后。     

血浆uPA、PAI-1浓度与食管鳞状细胞癌临床病理因素的相关性

目的：探讨血浆尿激酶型纤溶酶原激活物（urokinase-type plasminogen activator,uPA）、纤溶酶原激活物抑制剂-1（plasminogen activator inhibitor type-1,PAI-1）浓度作为食管鳞状细胞癌预后指标的可能性。方法：收集20例健康人、54例食管鳞状细胞癌患者（手术前、后）及14例术后复发转移患者血浆标本,采用ELISA法测定其血浆uPA、PAI-1浓度,并分析血浆uPA、PAI-1浓度与食管鳞状细胞癌患者临床病理特征的关系。结果：健康人群血浆uPA、PAI-1浓度显著低于食管鳞状细胞癌患者手术前及手术后血浆uPA、PAI-1浓度（P〈0.05）。食管鳞状细胞癌患者手术前血浆uPA、PAI-1浓度显著高于术后血浆uPA、PAI-1浓度（P〈0.05）,显著低于术后复发转移患者血浆uPA、PAI-1浓度（P〈0.05）。食管鳞状细胞癌患者血浆uPA、PAI-1浓度与年龄、性别无关,不同性别及年龄组间差异无显著性（P〉0.05）。与临床分期有关,临床分期越晚,浓度越高（P〈0.05）。与组织分化程度有关,分化程度越低,浓度越高（P〈0.05）。与有无淋巴结转移有关,有淋巴结转移组显著高于无淋巴结转移组（P〈0.05）。结论：uPA、PAI-1在食管鳞状细胞癌进展过程中发挥重要作用,血浆浓度可作为食管鳞状细胞癌的预后判断指标,浓度升高提示预后不良。     

Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer.

PURPOSE: Urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor (PAI)-1, have been shown to be related to poor prognosis in a variety of malignant solid tumors. Studies on the prognostic relevance of uPA and PAI-1 in ovarian cancer, however, have been inconclusive. The current study tests the hypothesis that elevated expression of uPA and PAI-1 is associated with prognosis and disease progression. EXPERIMENTAL DESIGN: uPA and PAI-1 were prospectively measured by quantitative ELISA in tumor samples from 103 ovarian cancer patients (82 primary invasive epithelial carcinomas, 9 low malignant potential tumors, and 12 recurrent ovarian carcinomas). RESULTS: uPA but not PAI-1 levels were consistently associated with malignant progression, with levels increased from low malignant potential tumors to primary tumors (uPA, P = 0.04; PAI-1, P = 0.019), from early to advanced disease stages (uPA, P = 0.014; PAI-1, P = 0.23), and from primary to intra-abdominal metastatic tumors (uPA, P = 0.001; PAI-1, P = 0.16). High uPA and PAI-1 levels were associated with residual tumor volumes of >1 cm (P = 0.001 and P = 0.016, respectively). Among invasive International Federation of Gynecologists and Obstetrician stages I-IV tumors, elevated levels of uPA (>5.5 ng/mg) and PAI-I (>18.8 ng/ml) were associated with a shortened progression-free survival (uPA, P = 0.003; PAI-1, P = 0.039) and overall survival (uPA, P = 0.0002; PAI-1, P = 0.007). In multivariate analysis, uPA retained prognostic independence for progression-free survival (P = 0.037) and overall survival (P = 0.006). CONCLUSIONS: These data suggest that the uPA/PAI-1 axis may play an important role in the intra-abdominal spread and reimplantation of ovarian cancer cells. The prognostic relevance of uPA and PAI-1 supports their possible role in the malignant progression of ovarian cancer.     

Plasminogen activator inhibitor-1 is an independent poor prognostic factor for survival in advanced stage epithelial ovarian cancer patients

High levels of plasminogen activator inhibitor-1 (PAI-1) in tissue extracts have been associated with poor prognosis in many epithelial cancers. Ovarian cancers contain a higher concentration of PAI-1 than benign ovarian tumors or normal ovaries. Reports, however, on the prognostic value of PAI-1 content in ovarian cancers have been conflicting. We used immunohistochemistry to study the primary and metastatic tissues from 131 epithelial ovarian cancer cases. This group has been previously characterized for the expression of urokinase (uPA), uPA receptor, PAI-2 and macrophage colony-stimulating factor (CSF-1). The intensity and extent of staining for PAI-1 in the tumor epithelium was scored. Kaplan-Meier curves of survival were compared using the log-rank test. The Cox regression model was utilized for multivariate analysis. Approximately 50% of the primary tumors and metastases expressed PAI-1. Among invasive stages III and IV patients, those whose primary tumors expressed PAI-1 had a shorter overall survival. The combination of strong expression of PAI-1 and expression of uPA was a highly significant factor for short disease-free and overall survival. Similar results were seen with the combination of high PAI-1 and low PAI-2 expression. Strong PAI-1 expression was significantly associated with expression of uPA receptor or CSF-1 in the tumor epithelium, but not with standard clinical parameters, and was an independent prognostic factor for poor survival on multivariate analysis. Our results show that PAI-1 expression in the primary tumor epithelium is an independent poor prognostic factor for survival, underscoring the tumor protective role of PAI-1 in ovarian cancer biology. Int. J. Cancer (Pred. Oncol.) 79:449–454, 1998.© 1998 Wiley-Liss, Inc.     

Expression of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in benign,borderline, malignant primary and metastatic ovarian tumors

Elevated levels of expression of the urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 have shown to be related to poor prognosis in a variety of cancer types. In the present study, cytosolic levels of uPA and PAI-1 were determined with enzyme-linked immunosorbent assays in cytosols prepared from 244 human ovarian tissues of different histological sub-types. Both uPA and PAI-1 were significantly associated with the malignant progression of ovarian tissues; the levels were increased going from normal tissue, via benign and borderline adenomas, to primary and metastatic adenocarcinomas. For the 90 patients (34 early-stage and 56 patients with advanced disease) from whom the primary adenocarcinoma tissues were examined, uPA and PAI-1 levels were evaluated for their association with clinicopathological parameters and with progression-free and overall survival. Neither uPA nor PAI-1 were significantly associated with the age of the patient, FIGO stage, tumor grade, tumor rest, the presence of ascites, or with progression-free or overall survival. On the other hand, age, FIGO stage/tumor rest and the presence of ascites, were significantly related to the length of both progression-free and overall survival in univariate analyses. Tumor grade was of prognostic significance in the analysis for progression-free survival, but not for overall survival. After adjustment for FIGO stage/tumor rest, only age retained its prognostic significance, in the analysis for progression-free survival and in that for overall survival. © 1996 Wiley-Liss, Inc.     

High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer.

Previous studies including various tumor types have shown different associations between tumor tissue levels of plasminogen activator inhibitor 2 (PAI-2) and patient survival. High tumor tissue concentrations of PAI-2 have been associated with good prognosis in patients with breast cancer, small cell lung cancer and ovarian cancer, but with poor histologic differentiation and poor prognosis in patients with colorectal cancer. On the other hand, high tumor tissue concentrations of urokinase plasminogen activator (uPA), uPA receptor (R) and PAI-1 have more consistently been associated with poor histologic differentiation and poor prognosis. Our study quantified PAI-2 and uPAR using specific enzyme-linked immunosorbent assays in homogenates of 274 samples of endometrial cancer tissue. The prognostic power of each factor was analyzed in the subgroup of patients with early stage disease, i.e., International Federation of Gynecology and Oncology (FIGO) surgical stage I-II (n = 188). This group had a median follow-up time of 6.8 years (range 0.7-9.9), and 23 progressions were observed. The 80(th) percentile for PAI-2 and uPAR was used to dichotomize the material, and the results were analyzed for associations with clinical data including progression-free survival. The results were also compared with DNA ploidy status, S-phase fraction, uPA and PAI-1, which we reported in a previous study (Fredstorp Lidebring et al., Eur J Cancer 2001; in press). A high PAI-2 level was associated with shorter progression-free survival in univariate analysis and was an independent prognostic factor in bivariate analyses, which included PAI-1, uPA and DNA ploidy status. In contrast, a high level of uPAR had no association with prognosis in early stage endometrial cancer. The combination of high PAI-2 and PAI-1 levels in tumors revealed a small group of stage I-II patients with an accumulative progression rate of 50%.     

Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer.

PURPOSE: In the present study, we investigated the association between tumor tissue levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and prognosis in patients with primary breast cancer and analyzed whether TIMP-1 may be useful as a prognostic marker in combination with urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1). EXPERIMENTAL DESIGN: In cytosolic extracts of 2984 primary breast tumors, total levels of TIMP-1 were determined using an established, validated ELISA. Levels of uPA and PAI-1 have previously been determined in the extracts. RESULTS: Univariate survival analysis showed a significant relationship between higher levels of TIMP-1 (continuous log-transformed variable) and poor prognosis [recurrence-free survival (RFS), overall survival (OS); P < 0.001]. Performing isotonic regression analysis, we identified a cut point to classify tumors as TIMP-1-low or TIMP-1-high. Using this cut point, high levels of TIMP-1 were significantly associated with shorter survival in univariate analysis, both in the total patient group (RFS, OS; P < 0.001), in the node-negative subgroup (RFS, hazard ratio = 1.28, P = 0.006), and in the node-positive subgroup (RFS, hazard ratio = 1.43, P < 0.001). In multivariate analysis, including uPA and PAI-1, TIMP-1 was significantly associated with shorter RFS, both when included as a continuous log-transformed (P = 0.03) and as a dichotomized variable (P = 0.002). CONCLUSIONS: This study validates previous findings that tumor tissue levels of TIMP-1 are associated with prognosis in patients with primary breast cancer. It confirms that TIMP-1 may be useful as a prognostic marker in combination with uPA/PAI-1 and adds substantial positive information on the use of TIMP-1 as a prognostic marker in breast cancer.     

Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc

Strong evidence has accumulated on the prognostic value of tumour-associated proteolytic factors in patients afflicted with solid malignant tumours, including advanced ovarian cancer. We evaluated the prognostic impact of the protease urokinase plasminogen activator (uPA) and its inhibitor PAI-1 on overall survival in patients with advanced ovarian cancer stage FIGO IIIc in order to select patients at risk. uPA and PAI-1 antigen were determined by ELISA in primary tumour tissue extracts of 86 ovarian cancer patients FIGO stage IIIc enrolled in a prospective study. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The time-varying coefficient model of Gray was used to assess the time-dependent strength of prognostic factors tumour mass, uPA and PAI-1 on overall survival. In all patients, uPA and PAI-1 (optimized cut-offs of 2.0 and 27.5 ng mg(-1) protein respectively), in addition to the traditional prognostic parameters of residual tumour mass, nodal status, grading and ascites volume, were of prognostic significance in univariate analysis for overall survival. Even in patients with residual tumour mass (n = 43), the statistically independent prognostic impact of PAI-1 persisted, allowing further discrimination between low- and high-risk patients. In multivariate analysis, residual tumour mass (P < 0.001, relative risk (RR) 4.5), PAI-1 (P < 0.001; RR 3.1) and nodal status (P = 0.022, RR 2.6) turned out to be strong, statistically independent prognostic parameters. Evaluation of the time-dependent prognostic impact of residual tumour mass and PAI-1 on overall survival (n = 86, 50 months) revealed that the prognostic power of these factors increased with time. In patients with advanced ovarian cancer, both residual tumour mass and PAI-1 are statistically independent strong prognostic factors. Even within patient subgroups with or without residual tumour mass, PAI-1 allowed selection of patients at risk who might benefit from individualized therapy protocols.     

Her-2/neu and urokinase-type plasminogen activator and its inhibitor in breast cancer.

PURPOSE: Recent studies suggest that HER-2/neu specifically promotes the invasive capacity of tumor cells by up-regulating secretion of the proteolytic enzyme, urokinase-type plasminogen activator (uPA), or its inhibitor, plasminogen activator inhibitor-1 (PAI-1), in colon and gastric cancer. It was the purpose of this study to: (a) evaluate the association between HER-2/neu and uPA and PAI-1 expression in a large primary breast cancer cohort; (b) perform the first multivariate analysis, including HER-2/neu, uPA, and PAI-1 in breast cancer; and (c) define the effect of HER-2/neu overexpression on uPA and PAI-1 expression in breast cancer cells. EXPERIMENTAL DESIGN: HER-2/neu, uPA, and PAI-1 were measured as continuous variables by ELISA in primary breast cancer tissue extracts from 587 patients with clinical follow-up and analyzed for correlations with clinical outcome. Furthermore, a full-length human HER-2/neu cDNA was introduced into five human breast cancer cell lines to define the effects of HER-2/neu overexpression on uPA and PAI-1 expression. In addition, we tested whether HER-2/neu antibodies could reverse any given alteration of uPA and PAI-1 levels. RESULTS: Our findings indicate a weak positive association between HER-2/neu and uPA (r = 0.147; P < 0.001) and no association between HER-2/neu and PAI-1 (r = 0.07; P = 0.085). HER-2/neu overexpression (> or =400 fmol/mg) and high levels of uPA/PAI-1 (> or =5.5 ng/mg and/or > or =14 ng/mg, respectively) were significantly associated with shorter disease-free survival (DFS; P < 0.001 and P = 0.003) and metastasis-free survival (MFS; P = 0.015 and P < 0.001). Multivariate analysis revealed prognostic independence between HER-2/neu and the uPA/PAI-1 axis for DFS and MFS. Both uPA and PAI-1 had no significant discriminatory effect among HER-2/neu-positive patients for DFS. The prognostic value of HER-2/neu overexpression for MFS, however, was significantly enhanced by elevated uPA expression (P = 0.053). Stable transfection of the HER-2/neu gene into multiple human breast cancer cell lines resulted in consistent down-regulation of uPA or PAI-1 expression. In addition, anti-HER-2/neu antibodies did not significantly affect uPA or PAI-1 expression in human cancer cell lines naturally overexpressing HER-2/neu. CONCLUSIONS: The present findings suggest that the invasive phenotype elicited by HER-2/neu overexpression in breast cancer is not a direct effect of uPA or PAI-1 expression. HER-2/neu and the uPA/PAI-1 axis have been shown to affect the invasive capacity of breast cancer independently. Determination of uPA can provide significant additional prognostic information for MFS in HER-2/neu-positive and -negative patients.     

Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer

BACKGROUND AND OBJECTIVES: Certain pathophysiological markers may be helpful in selecting further therapies for patients with resected colorectal cancer (CRC). The aim of this study was to determine whether expression of proteins of the plasminogen activation system (PAS), which are important in tumor spread and growth, can predict outcome of human CRC. METHODS: Protein expression of the PAS, including urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2), was determined in the colonic tissue samples of 56 patients with resected primary CRC by quantitative immunohistochemistry and correlated with clinicopathological parameters and patient outcome. RESULTS: Overexpression of uPA (t-test, P < 0.001), uPAR (P < 0.001) and PAI-1 (P = 0.031) was significantly associated with liver metastatic CRC tumors. Higher uPA or uPAR expression level was significantly correlated with overall survival (OS; log-rank, P = 0.001 and P < 0.0001) and cancer-specific survival (CSS; P = 0.001 and P < 0.0001) after the first CRC resection. The predictive value of both uPA and uPAR in liver metastasis, OS and CSS was independent from other parameters (multivariate Cox regression: all P < 0.001). CONCLUSIONS: uPA and uPAR may be independent predictors of liver metastasis, patient overall survival and cancer-specific survival after resection of colorectal tumors.     

Predictive impact of urokinase-type plasminogen activator: plasminogen activator inhibitor type-1 complex on the efficacy of adjuvant systemic therapy in primary breast cancer

One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system. This system comprises of, among others, the urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1). In this study we investigated whether the uPA:PAI-1 complex is associated with the responsiveness of patients with primary breast cancer to adjuvant systemic therapy. Quantitative enzyme-linked immunosorbent assays were used to assess the levels of uPA, PAI-1, and uPA:PAI-1 complex in 1119 tumors of patients with primary invasive breast cancer. These patients were followed for a median follow-up time of 59 months (range, 2-267 months) after the primary diagnosis. Correlations with well-known clinicopathological factors, and univariate and multivariate survival analyses were performed. High uPA:PAI-1 complex levels were correlated with an adverse histological grade, and inversely associated with negative estrogen and progesterone receptor status. High tumor levels of uPA:PAI-1 complex predicted an early relapse in the univariate relapse-free survival analysis (P < 0.001). The multivariate analysis showed that high uPA:PAI-1 complex levels were associated with a decreased relapse-free survival time (P = 0.033), independently of age, tumor size, number of lymph nodes affected, progesterone receptor status, uPA, adjuvant endocrine, and chemotherapy. More important, it was demonstrated that there is a larger benefit from adjuvant chemotherapy for patients with higher versus lower tumor levels of uPA:PAI-1 complex. The results of this study imply that the expression of uPA:PAI-1 complex independently predicts the efficacy of adjuvant chemotherapy in patients with primary breast cancer.