Expression and prognostic significance of urokinase and plasminogen activator inhibitor type-1 in endometrial hyperplasia and cancer

Proteolytic enzymes, like urokinase (uPA) and plasminogen activator inhibitor type-1 (PAI-1), are involved in remodelling tissues during invasion and metastasis of tumor cells. The purpose of the study is to evaluate the expression and the prognostic significance of these enzymes in endometrial hyperplasia and cancer. We used immunohistochemical staining to localize uPA and PAI-1 antigens and evaluate their expression, and the enzyme-linked immunosorbent assay (ELISA) to measure their levels during the progression of endometrial carcinoma. The results show that the levels of uPA and PAI-1 detection are systematically weak in simplex hyperplasia and are moderate in complex hyperplasia. In the endometrial carcinoma a very strong reaction was observed in the most aggressive variant of epithelial tumors. A positive signal for uPA was found only in the cytoplasm of normal and hyperplastic cells while, in tumors, uPA was present also in the cellular areas surrounding the neoplastic glands and at the apex of the malignant cells. The PAI-1 immunoreactivity was weak to moderate in 95.4% of carcinomas, with a diffuse signal mostly distributed in the cytoplasm of neoplastic cells and tumor stroma. UPA antigen concentrations were significantly higher in endometrial carcinoma than in endometrial hyperplasia (p<0.05) and in normal endometrium (p<0.001). PAI-1 antigen concentrations in carcinoma samples were significantly higher than in normal endometrium (p=0.002), but the difference was not statistically significant with respect to that in endometrial hyperplasia. We did not find any correlation between uPA and PAI-1 concentrations and the standard prognostic parameters for evaluating endometrial carcinoma. In conclusion, this study demonstrates that in hyperplastic endometria and in endometrial carcinoma there is a progressive increase in expression of uPA and PAI-1 than in normal endometrial tissue. In carcinoma tissues, the high expression of uPA is unregulated in the surrounding stroma tissue, particularly in the most aggressive histopathologic variants. UPA and PAI-1 may be factors associated with invasive behavior in endometrial carcinoma independent of other clinicopathological parameters.     

子宫内膜腺癌组织中尿激酶型纤溶酶原激活系统的表达及其临床意义

目的：研究尿激酶型纤溶酶原激活系统在子宫内膜腺癌的发生、发展及浸润转移中的规律及其对临床的指导意义。方法：应用免疫组织化学方法测定24例正常子宫内膜、30例子宫内膜增生过长及62例子宫内膜腺癌组中uPA、uPAR、PAI-1的表达,并分析与良恶性、临床分期、组织学分级、基层浸润深度及淋巴结转移的关系。结果：uPA、uPAR、PAI-1在子宫内膜腺癌组中的表达较正常子宫内膜组和子宫内膜增生过长组中的表达显著升高（P均〈0．05）,而正常子宫内膜组和子宫内膜增生过长组中的表达无显著性差异（P〉0．05）。uPA、uPAR、PAI-1的高表达与肿瘤分化、临床分期、肌层浸润深度和淋巴结转移有关（P〈0．05）。结论：uPA、uPAR、PAI-1的表达与子宫内膜腺癌的发生、发展及浸润转移密切相关,可作为判断预后的重要指标。     

子宫内膜癌中uPA、p-p38和VEGF的表达及意义

目的:检测子宫内膜癌组织中uPA、p-p38和VEGF表达情况并探讨其意义.方法:采用免疫组织化学SP法检测60例子宫内膜癌、32例正常子宫内膜组织中三者的表达.结果:子宫内膜癌组织中uPA、p-p38和VEGF分别表达定位于细胞核和细胞膜,其阳性表达率分别为51.67％(31/60)、55.00％(33/60)和43.33％(26/60)明显高于正常子宫内膜组织0、0、12.50％(P＜0.05).三者的表达与肌层浸润程度、淋巴结转移、临床分期及病理分期有关(P＜0.05);在子宫内膜癌组织中uPA、p-p38和VEGF三者之间两两比较表达呈正相关(P＜0.05).结论:uPA、p-p38和VEGF在子宫内膜癌呈高表达,与子宫内膜癌的发生、发展和转移密切相关.     

Urokinase Receptor and Vascular Endothelial Growth Factor Are Synergistically Associated with the Liver Metastasis of Colorectal Cancer

Considering recent findings that the urokinase plasniinogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute Synergistically to the liver metastasis of colorectal cancer.     

Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer.

Considering recent findings that the urokinase plasminogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute synergistically to the liver metastasis of colorectal cancer.     

Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer

Urokinase plasminogen activating system (PA system) and vascular endothelial growth factor (VEGF) were recently suggested to contribute synergistically to tumor progression. To evaluate the roles of the PA system and VEGF in gastric cancer, the effects of the PA system and VEGF on tumor angiogenesis and the survival of patients with gastric cancer were investigated. Cancer tissues from 101 gastric cancer patients were assayed immunohistochemically for expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), PA inhibitor-1 (PAI-1) and VEGF protein. The positive rates of uPA, uPAR, PAI-1, VEGF expression were 22.8%, 32.7%, 36.6% and 26.7%, respectively. Positive staining was observed in tumor cells (uPA, uPAR, VEGF), or in both tumor cells and stromal cells (PAI-1). The expressions of uPA, uPAR, PAI-1 and VEGF were significantly correlated with the clinicopathological factors: uPA, depth of tumor invasion, differentiation, lymphatic and vascular invasion; uPAR, tumor size, depth, lymph node involvement, differentiation, vascular invasion; PAI-1, tumor size, depth, lymph node involvement, differentiation, vascular invasion; VEGF, differentiation, vascular invasion. The microvessel density (MVD) assessed immunohistochemically was significantly higher in the patients with expression of uPA, uPAR or VEGF, and stepwise analysis identified uPA as an independent correlated factor with MVD. Furthermore, multivariate analysis demonstrated that depth of tumor invasion, lymph node involvement and uPA expression were independent prognostic factors. uPA is a key factor in the PA system, being associated with a poor outcome of gastric cancer, and contributing not only to invasive activity, but also to angiogenesis. (Cancer Sci 2003; 94: 43–49)     

Measurement of plasminogen activator system components in plasma and tumor tissue extracts obtained from patients with breast cancer: an EORTC Receptor and Biomarker Group collaboration

The plasminogen activator (PA) system comprises the 2 serine proteases, urokinase PA (uPA) and tissue PA (tPA), the 2 serpin inhibitors, PAI-1 and PAI-2 and the uPA receptor (uPAR; CD87). High levels of uPA, PAI-1, uPA-PAI-1 complex and uPAR in breast cancer tissue are associated with poor prognosis, while high levels of tPA or PAI-2 correlate with good prognosis. In this study, pre-operative plasma levels of uPA, PAI-1, uPAR, tPA, uPA-PAI-1 complex, and tPA-PAI-1 complex were measured in patients with benign (n=103) and malignant breast disease (n=113) by immunoenzymatic assays (ELISA). While plasma antigen levels of uPA, PAI-1, uPA-PAI-1 complex and uPAR were not significantly different in the 2 groups, antigen levels of tPA and tPA-PAI-1 complex were significantly higher in patients with breast carcinoma compared to the control group. In plasma from the breast cancer patients, uPA levels correlated weakly but significantly with those of tPA (r=0.20, p=0.035) and uPAR (r=0.208, p=0.028). tPA levels correlated strongly with tPA-PAI-1 complex (r=0.972, p=0.0001) while uPA-PAI-1 levels were significantly associated with PAI-1 levels (r=0.534, p<0.0001), tPA levels (r=0.348, p=0.0003) and tPA-PAI-1 levels (r=0.356, p=0.002). However, no significant correlation was found between plasma and tumor tissue levels of uPA, PAI-1, uPA-PAI-1 complex, tPA or tPA-PAI-1. Our findings indicate that determination of these factors in plasma do not reflect their concentration in tumor tissue. Therefore, measurement of PA components in blood cannot be recommended for assessing prognosis in breast cancer.     

Significance of plasminogen-activation system in the formation of macroscopic types and invasion in esophageal carcinoma

BACKGROUND: The roles of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the formation of macroscopic types and invasion were investigated. MATERIALS AND METHODS: A total of 40 surgically-resected esophageal carcinoma tissues were immunohistochemically stained, and the expression of uPA, PAI-1 and the uPA/PAI-1 ratio, were evaluated. RESULTS: The expression of uPA was significantly stronger in the macroscopically infiltrative type (n = 20: p = 0.0027), whereas PAI-1 was significantly stronger in the localized type (n = 20: p = 0.0005). The uPA/PAI-1 ratio was significantly higher in the infiltrative type (p < 0.0001). A significant correlation was found between the U/P ratio and the depth of tumor invasion (r = 0.511, p = 0.0014). Analysis of tumors of uniform size (4.0-6.0 cm in length), showed that the depth of invasion was significantly greater in the infiltrative type (p = 0.0038). CONCLUSION: The results demonstrated that uPA and PAI-1 play important roles in invasion and formation of macroscopic types of esophageal carcinoma.     

Prognostic significance of proteolytic enzymes in human brain tumors

Summary Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n=82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n=50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA.Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon, lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.     

Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 and type 2 in stage I malignant melanoma

The urokinase-type plasminogen activator (uPA) and its inhibitors type 1 (PAI-1) and type 2 (PAI-2) are considered to have a key role in the process of invasion and metastasis. We investigated the differences in uPA, PAI-1 and PAI-2 concentrations in primary cutaneous melanoma and normal skin and correlations with well-established melanoma prognostic factors. The study was performed on 43 patients (19 men, 24 women; mean age 57 years) with histologically confirmed primary melanomas <1.5 mm thick. The uPA concentrations were determined in 36 pairs of triton extracts, and the PAI-1 and PAI-2 concentrations in 43 pairs of cytosols prepared from the tumour and adjacent normal tissue samples (matched pairs). The uPA, PAI-1 and PAI-2 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Significantly higher concentrations of both uPA and PAI-1 were measured in melanomas than in normal surrounding skin (uPA: 1.08 vs 0.48 ng/mg total protein (mgp), p<0.001; PAI-1: 14.07 vs 2.07 ng/mgp, p<0.001). The melanoma uPA, PAI-1 and PAI-2 concentrations correlated significantly (p<0.05) with normal skin (r=0.73, 0.54, 0.38 respectively). The uPA concentrations positively correlated with those of PAI-1 measured in melanomas (r=0.45, p<0.01). PAI-1 values were significantly lower (p<0.001) in the melanomas of Breslow thickness < or =0.75 mm, Clark invasion 0.75 mm, Clark invasion of > or =II and < or =III, with microscopic ulceration and vascular invasion (22.25, 17.67, 27.67, 37.77, respectively). Determination of uPA and PAI-1 can provide significant additional prognostic information for melanoma patients.     

上皮性卵巢癌组织中uPA和PAI-1的表达及意义

背景与目的:近年研究表明,尿激酶型纤溶酶原激活物(urokinase-type plasminogen activator,uPA)及其抑制物(plasminogen activator inhibitor,PAI)在肿瘤侵袭、转移过程中起重要作用,但其与上皮性卵巢癌的关系研究甚少.本研究从蛋白水平探讨uPA、PAI-1在上皮性卵巢癌浸润、转移中的作用,组织中的分布情况、及与预后的关系.方法:应用免疫组化法检测80例上皮性卵巢癌、20例良性卵巢肿瘤组织uPA、PAI-1蛋白表达,并结合临床病理因素、预后进行分析.结果:上皮性卵巢癌、良性卵巢肿瘤组织中uPA阳性率分别为77.5%和30.0%(P＜0.001),PAI-1阳性率分别为55.0%和20.0%(P=0.005).上皮性卵巢癌组织中uPA表达与PAI-1表达呈显著性正相关(P=0.001).uPA阳性与盆腹腔转移病灶直径＞1 cm有关(P=0.038),与患者年龄、FIGO分期、组织学类型、病理分级、术前血CA125值、卵巢病灶大小、残留病灶大小无显著性相关(P＞0.05);PAI-1阳性与FIGO分期有显著性相关(P=0.022),与上述其他临床病理因素无显著性相关(P＞0.05).多因素Cox回归模型显示,uPA表达是肿瘤无进展生存、总生存的独立危险因素:PAI-1表达是总生存的独立危险因素.结论:上皮性卵巢癌组织中uPA、PAI-1表达上调.uPA、PAI-1有可能作为预测上皮性卵巢癌预后的参考指标.     

Detection of plasminogen activators in oral cancer by laser capture microdissection combined with zymography

Plasminogen activation is believed to be critical to the progression of oral squamous cell carcinoma by facilitating matrix degradation during invasion and metastasis, and high levels of urokinase plasminogen activator (uPA) and plasminogen activator (PA) inhibitor-1 (PAI-1) in tumors predict poor disease outcome. We describe the development of a novel method for studying PA in oral cancer that combines the sensitivity and specificity of zymography with the spatial resolution of immunohistochemistry. Laser capture microdissection (LCM) was combined with plasminogen–casein zymography to analyze uPA, tissue PA (tPA), uPA–PAI-1 complexes, and tPA–PAI-1 complexes in 11 tumors and adjacent non-malignant epithelium from squamous cell carcinomas of the tongue, floor of mouth, larynx, and vocal cord. uPA was detectable in all tumor samples analyzed, uPA–PAI-1 complexes in three samples, and tPA in nine. PA was detectable in as little as 0.5 μg protein lysate from microdissected tumors. In all specimens, uPA expression was highly increased in tumor tissue compared to adjacent non-malignant tissue. In conclusion, LCM combined with zymography may be excellently suited for analyzing the prognostic significance and causal involvement of the plasminogen activation system in oral cancer.     

晚期肺癌患者凝血-纤溶系统的变化及化疗对其的影响

目的 探讨尿激酶纤维蛋白溶酶原激活物(urokinase plasminogen activator, uPA）系统在肺癌 患者中的变化,分析并评价其与肺癌患者预后的关系。方法 记录肺癌患者化疗前、后及对照组的凝 血指标,并用ELISA法检测各组外周血uPA、 组织型纤维蛋白溶酶原激活物（tissue-type Plasminogen Activator, tPA）、纤维蛋白溶酶原激活剂抑制物-1（Plasminogen Activator Inhibitor-1, PAI-1）浓度。结 果 （1）肺癌患者化疗前(A1组)、化疗2周期后(A2组)上述各项凝血-纤溶指标均显著高于正常对照 组(B组)( P均 < 0.05);（2）A1组与A2组之间的凝血指标血小板计数（platelet count, PC）、凝血酶原 时间（prothrombin time, PT）、活化部分凝血活酶时间（activated partial thromboplastin time, APTT） 虽然存在差别,但差别不具有统计学意义(P均 >0.05),化疗2周期后的D-二聚体（D-dimer）、tPA、 uPA、PAI-1均显著高于化疗前(P均<0.05);（3）分层分析表明：A2组中治疗进展病例的uPA和 D-dimer显著高于临床获益病例(P 均<0.05); （4）化疗前、后有显 著变化的纤溶指标uPA与D-dimer、 tPA、PAI-1之间均有直线正相关性 (0.472、0.624、0.575、P 均<0.01), tPA与PAI-1也具有直线正相关关系 (r=0.61,P <0.001)。结论 （1） 肺癌患者存在凝血-纤溶系统紊乱,化疗可以加重这一异 常,且纤溶系统变化更为敏感;（2）血浆低水平的uPA和 D-dimer的肺癌患者有较好化疗效果,且两者存在正相关关 系,因此两者可能成为提示肺癌患者预后的指标。     

Clinical implications of urokinase and tissue type plasminogen activators and their inhibitor (PAI-1) in breast cancer tissue

Cytosol of primary breast cancers from 217 women of predominantly Arab ethnicity were assayed for uPA, tPA, PAI-1 and a subset for ER, PR and pS2. Serum levels of CEA and CA153 were determined during follow-up. Only tPA correlated to nodal status and tumour grade, and PAI-1 to clinical stage. PAI-1 was related to uPA and both were inversely correlated with PR and pS2 (PAI-1 also to ER). Conversely tPA was directly correlated with ER, PR and pS2. Women with high tumour uPA and PAI-1, but not tPA, had shorter overall, and relapse-free, survival. Only nodal status and clinical stage were independent predictors in multivariate analysis. However, uPA and PAI-1 were more prognostically informative than ER or PR and their usefulness may extend to delineation of patients likely to respond to adjuvant therapy.     

Production and post-surgical modification of VEGF, tPA and PAI-1 in patients with glioma

Malignant gliomas are associated with risk of thromboembolism, but the molecular link between tumor and peripheral pro-coagulant status has not been elucidated. Vascular Endothelial Growth Factor (VEGF), tissue-type Plasminogen Activator (tPA), Plasminogen Activator Inhibitor-1 (PAI-1) and lipoprotein (lp) (a) influence the pro-coagulant status. To assess whether the presence of the tumor influenced the peripheral levels of VEGF, tPA, PAI-1 and lp(a), we studied the expression and secretion of VEGF, tPA, PAI-1 and lp(a) in glioma specimens, in peripheral blood and in primary glioma-derived cultures. We also measured lp(a), VEGF, tPA and PAI-1 in the peripheral circulation of patients, before and after surgery for glioma. VEGF, tPA and PAI-1 were expressed in glioma specimens. Glioma cells were indeed a major source of tPA and PAI-1; these molecules were significantly more expressed in glioma than in patient's blood cells. Lp(a) was rarely expressed in glioma specimens and not expressed in blood cells. In glioma, VEGF, tPA and PAI-1 were localized mainly in tumor cells; tPA was localized also in the extracellular matrix and PAI-1 in tumor vascular lumen. Glioma cells were indeed able to produce and release VEGF, tPA and PAI-1. After surgery, peripheral levels of VEGF and PAI-1 were increased, while tPA and lp(a) were unchanged. The great amount of VEGF, tPA and PAI-1 produced by glioma could influence peripheral levels of these molecules. The partial resection of the tumor by surgery was not able to decrease plasma levels of these molecules.     

Proteases associated with gynecological tumors

Proteases are involved in the invasion and metastasis of tumours by destruction of the basal membrane and connective tissue. As levels in malignant tissue have both prognostic and therapeutic implications, we examined 318 frozen samples from malignant tumours and comparable non-malignant tissue looking for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) levels with ELISA, as well as cathepsin D with RIA. Oestrogen receptor (ER) levels, progesterone receptor (PrgR) levels and epidermal growth factor receptors (EGFR) were measured by biochemical methods at the same time. Significantly raised levels of uPA, PAI-1 and cathepsin D were found in malignant tissue, with PAI-1 particularly high in carcinoma of the cervix. Significantly raised tPA levels were found in breast cancer tissue with a more favourable clinical prognosis, with a positive correlation between tPA and ER. No correlation could be shown between uPA, PAI-1 and cathepsin D with other prognostic factors for breast cancer. It could be that routine, uncomplicated estimation of tumour-associated proteases such as uPA, tPA, PAI-1 and cathepsin D will provide an independent prognostic marker for therapeutic decisions with regard to gynaecological tumours and breast cancer.     

非小细胞肺癌淋巴结转移相关因素的研究

目的：检测尿激酶纤溶酶原激活物（uPA）、尿激酶纤溶酶原激活物抑制剂（PAI-1）、血管内皮生长因子（VEGF）和微m管密度（MVD）在非小细胞肺癌（NSCLC）组织中的表达以及与淋巴结转移的关系。方法：采用免疫组织化学方法联合检测52例NSCLC组织中uPA、PAI—1、VEGF和MVD的表达水平。结果：uPA、PAI—1、VEGF和MVD在NSCLC中的表达显著高于正常肺组织，影响淋巴结转移的相关因素是TNM分期（P〈0．001）、肿瘤侵犯程度（P=0．034）、uPA表达（P=0．048）、VEGF表达（P=0．047）。多因素分析表明VEGF高表达是淋巴结转移的独立影响因素（P=0．043）。结论：uPA、VEGF高表达与NSCLC的淋巴结转移密切相关，促进了肿瘤转移。     

Genetic and plasma markers of venous thromboembolism in patients with high grade glioma.

PURPOSE: Deep venous thrombosis/pulmonary embolism (DVT/PE) is a frequent complication in the course of cancer, particularly in brain tumors. We investigated genetic and plasma factors possibly associated with risk of DVT/PE in patients with high-grade glioma. EXPERIMENTAL DESIGN: In a case-control study, we studied polymorphisms of the genes coding for factor II (G20210A), factor V (G1691A), methylenetetrahydrofolate-reductase (C677T), tissue-type plasminogen activator (tPA; insertion/deletion), plasminogen activator inhibitor-1 (PAI-1; 4G/5G), and vascular endothelial growth factor (VEGF; C936T). We also measured plasma levels of D-dimer, lipoprotein (lp) (a), homocysteine, VEGF, tPA, and PAI-1, comparing healthy control patients with patients with glioma or with patients with neurological nonneoplastic disease (multiple sclerosis). RESULTS: Genotype frequencies of polymorphisms analyzed were similar in patients with glioma and in healthy matched population. D-dimer, lp (a), homocysteine, VEGF, tPA, and PAI-1 plasma levels were significantly higher in patients with glioma than in healthy controls, whereas patients having neurological nonneoplastic disease had plasma values of these molecules not significantly different from healthy controls. VEGF, tPA, and PAI-1 were also found at high-plasma levels in patients carrying genotypes that, in healthy controls, were associated with "low-producing" phenotypes. CONCLUSIONS: Genetic risk factors alone did not explain the high incidence of DVT/PE observed in patients with glioma. Higher plasma levels of molecules influencing the coagulation pathways indicate that the tumor itself might confer an increased risk of DVT/PE; thus, D-dimer, homocysteine, lp (a), VEGF, tPA, and PAI-1 look like good candidates to be evaluated as DVT/PE prognostic factors.     

Plasminogen activator inhibitor type 2 in breast cancer.

The serine protease urokinase plasminogen activator (uPA) is causally involved in cancer invasion and metastasis. Activity of this protease in vivo is controlled principally by two inhibitors, one of which is plasminogen activator inhibitor type 2 (PAI-2). In this study, we show that PAI-2 levels were significantly higher in primary breast carcinomas (n = 152) than benign breast tumours (n = 18). In the primary cancers, PAI-2 levels correlated weakly but significantly with those of uPA and PAI-1, but not with tissue type plasminogen activator (tPA) or uPA receptor (uPAR) levels. Using Northern blotting, mRNA for PAI-2 was found in 28.6% of 49 primary breast cancers. In contrast to findings at the protein level, PAI-2 mRNA levels failed to correlate with those for uPA or PAI-1. After immunocytochemistry with primary cancers, PAI-2 was detected predominantly in the malignant cells of primary carcinomas but was also present in stromal cells. Using the median value as a cut-off point, PAI-2 showed no significant relationship with either disease-free interval or overall survival. However, using an optimum cut-off value, patients with low levels of PAI-2 had a worse outcome than those with a high level. We conclude that, unlike PAI-1, high levels of PAI-2 may be a favourable prognostic marker in breast cancer.     

结肠癌转移相关基因1与c-met在子宫内膜癌中的表达及其临床价值

目的:探讨MACC1与c-met蛋白在子宫内膜癌中的表达及其临床意义。方法:应用免疫组织化学方法检测45例子宫内膜癌组织、38例增生子宫内膜组织、20例正常子宫内膜组织中MACC1与c-met蛋白的表达情况,分析两者在不同子宫内膜中的表达率及其与子宫内膜癌临床病理参数的关系,并分析两指标在子宫内膜癌组织中表达的相关性。结果:MACC1与c-met在子宫内膜癌组织中的阳性表达率显著高于增生子宫内膜组织、正常子宫内膜组织（P＜0.05）。MACC1与c-met在子宫内膜癌组织中的表达与肌层浸润深度、手术病理分期、组织分化级别显著相关,而与年龄、肿瘤大小等无关。MACC1与c-met蛋白的表达呈正相关（P＜0.05）。结论:MACC1与c-met在子宫内膜癌组织中表达增高,肌层浸润较深、手术病理分期越晚、组织分化程度较低者表达率更高,两者与肿瘤的发生、发展、转移关系密切。