Dedifferentiation of serous ovarian cancer from cystic to solid tumors is associated with increased expression of mRNA for urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1)

The plasminogen activating system is involved in tumor growth and metastasis by degradation of extracellular matrix, and modulation of cell adhesion and migration. Benign and well-differentiated malignant ovarian tumors present as cystic lesions with preserved glandular morphology, whereas poorly differentiated tumors and metastases are solid with characteristic absence of glandular morphology. We analyzed the mRNAs for urokinase plasminogen activator (uPA), its receptor (uPAR), and inhibitor (PAI-1) in serous ovarian tumors by in situ hybridization and by densitometric scanning of Northern blots prepared from tissue extracts. The mRNA expressing cells in the in situ hybridization sections were evaluated and counted by two different observers. The number of mRNA expressing cells for uPA, uPAR and PAI-1 were all significantly increased in solid as compared with cystic malignant tumors. The increased expression of all three mRNA species was mainly located in the stroma of poorly differentiated tumors and metastases. Apart from being expressed in the stroma of these tumors, uPAR mRNA was also expressed by tumor cells located along the stromal/epithelial boarder. In addition, the tumor tissue content of uPA, uPAR and PAI-1 mRNAs as measured by Northern blots were higher in the solid as compared with the cystic tumors. Increased expression of uPA, uPAR and PAI-1 genes in the solid tumors suggest a correlation with a more aggressive phenotype.     

High expression of S100P is associated with unfavorable prognosis and tumor progression in patients with epithelial ovarian cancer

Accumulating evidence has demonstrated that S100P is involved in the tumorigenesis and progression of multiple cancers. In the current study, we evaluated the expression of S100P in epithelial ovarian cancer and assessed its relevance to clinicopathological characteristics. Moreover, we investigated the biological effects of S100P using A2780 and SKOV3 cells. S100P expression was significantly increased in epithelial ovarian cancer specimens compared with fallopian tube tissues and normal ovary tissues. And high expression of S100P in epithelial ovarian cancer samples was significantly associated with tumor stage (P<0.001), serum CA125 level (P=0.026), residual tumor (P<0.001), ascites (P<0.001) and lymph nodes metastasis (P<0.001). Multivariate Cox analysis showed that S100P expression was an independent prognostic factor of overall survival (OS) and progression free survival (PFS) (P=0.017 and 0.031, respectively). Functional assays showed that overexpression of S100P promoted cell proliferation and cell cycle progression but did not affect cell migration and invasion in A2780 and SKOV3 cells. These data suggest that S100P may contribute to tumor development in epithelial ovarian cancer and could be a useful marker for the prognosis of epithelial ovarian cancer patients.     

UPA蛋白表达与上皮性卵巢癌生物学行为的关系

目的：探讨尿激酶型纤溶酶原激活因子（UPA）的蛋白表达与上皮性卵巢癌生物学行为的关系。方法：15例正常卵巢组织、15例良性上皮性卵巢肿瘤组织,89例上皮性卵巢癌标本用免疫组化的方法检测UPA蛋白表达。结果：15例正常卵巢组织,UPA表达全部阴性。15例良性上皮性卵巢肿瘤组织,1例UPA阳性,14例阴性。89例上皮性卵巢癌,36例阴性,53例阳性。Stage（Ⅰ＋Ⅱ）的UPA阳性率为41.0%,Stage（Ⅲ＋Ⅳ）的阳性率为74.0%,Stage（Ⅲ＋Ⅳ）患者的阳性率明显高于Stage（Ⅰ＋Ⅱ）患者。病理分级G1、G2、G3的UPA阳性率分别为25%、59.8%、80.0%,由G1至G3UPA阳性率逐渐增高。卵巢癌原发灶的UPA阳性率是63.2%,转移病灶的阳性率是84.2%,转移灶的阳性率高于原发灶。结论：UPA表达水平有助于判断卵巢肿瘤的良、恶性。UPA表达与上皮性卵巢癌的浸润、转移密切相关。     

尿激酶受体在宫颈癌组织中的表达

目的研究宫颈癌患者尿激酶型纤溶酶原激活物受体(uPAR)在癌组织中的变化,初步探讨uPAR与宫颈癌浸润、转移及预后的关系。方法通过免疫组织化学SABC法检测uPAR在43例宫颈癌组织和10例正常宫颈组织的表达。结果将组织标本按病理学检查结果分为宫颈癌组和正常宫颈组,免疫组织化学结果提示宫颈癌组uPAR阳性表达率为65.12%,而正常宫颈组uPAR未见阳性表达,两组相比差异有统计学意义(P<0.01)。宫颈癌患者癌组织uPAR的表达与其临床分期、淋巴结是否转移具有相关性(P<0.05)。结论与正常宫颈组相比,宫颈癌患者癌组织uPAR呈异常高表达。uPAR在宫颈癌的生长、侵袭转移过程中可能起着重要的作用。检测其在组织中的表达有助于判断患者的病情及预后。     

尿激酶受体在宫颈癌组织中的表达

目的：研究宫颈癌患者尿激酶型纤溶酶原激活物受体（uPAR）在癌组织中的变化，初步探讨uPAR与宫颈癌浸润、转移及预后的关系。方法：通过免疫组织化学SABC法检测uPAR在43例宫颈癌组织和10例正常宫颈组织的表达。结果：将组织标本按病理学检查结果分为宫颈癌组和正常宫颈组，免疫组织化学结果提示宫颈癌组uPAR阳性表达率为65．12％，而正常宫颈组uPAR未见阳性表达，两组相比差异有统计学意义（P〈0．01）。宫颈癌患者癌组织uPAR的表达与其临床分期、淋巴结是否转移具有相关性（P〈0．05）。结论：与正常宫颈组相比，宫颈癌患者癌组织uPAR呈异常高表达。uPAR在宫颈癌的生长、侵袭转移过程中可能起着重要的作用。检测其在组织中的表达有助于判断患者的病情及预后。     

Metformin intake is associated with better survival in ovarian cancer

BACKGROUND:

The objective of this case‐control study was to identify any association of metformin intake with the survival of patients with ovarian cancer.

METHODS:

In this retrospective case‐control study, women with ovarian cancer who received metformin (cases) were compared with women with ovarian cancer who did not receive metformin (controls). A 2‐layered analysis was conducted. In preliminary analysis, all cases (the OC cohort) were compared with controls at a 1:2 ratio. Subsequently, in definitive analysis, only patients who had epithelial ovarian cancer (the EOC cohort) were compared with controls at a 1:3 ratio. In the EOC cohort, cases were matched with controls for age (±5 years), International Federation of Gynecology and Obstetrics stage, and residual disease. Prognostic variables and disease specific survival were compared using chi‐square tests, the Kaplan‐Meier (log‐rank) method, and Cox proportional hazards analysis.

RESULTS:

In a preliminary analysis of the OC cohort (72 cases and 143 controls), cases had better survival (5‐year disease‐specific survival for cases vs controls, 73% vs 44%; P = .0002). In the definitive analysis of the EOC cohort (61 cases and 178 controls), the distribution of age, disease stage, optimal cytoreduction, serous histology, and platinum chemotherapy remained similar between cases and controls (P > .05). Despite these similarities, cases had significantly better survival (5‐year disease‐specific survival for cases vs controls, 67% vs 47%; P = .007). On multivariate analysis, metformin remained an independent predictor of survival (hazard ratio, 2.2; 95% confidence interval, 1.2‐3.8; P = .007) after controlling for disease stage, grade, histology, chemotherapy, body mass index, and surgical cytoreduction.

CONCLUSIONS:

The results of this study indicated an association of metformin intake with survival in patients with ovarian cancer. The receipt of metformin was associated with better survival, and the authors concluded that metformin is worthy of clinical trials in ovarian cancer. Cancer 2013. © 2012 American Cancer Society.     

Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer.

PURPOSE: The aim of the study was to evaluate the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in preoperatively obtained sera samples (s-suPAR) from breast cancer patients. EXPERIMENTAL DESIGN: suPAR levels were determined by the use of a kinetic ELISA in sera from 274 breast cancer patients and in tumor cytosols (c-suPAR) from 188 of these patients. In addition, s-suPAR levels were analyzed in 174 female blood donors. RESULTS: The mean s-suPAR level was 3.8 ng/ml (range, 1.6-9.2 ng/ml) in the patients and 3 ng/ml (range, 1.3-6.4 ng/ml) in the donors. The mean c-suPAR level was 0.55 ng/mg protein (range, 0.07-2.83 ng/mg protein). A weak but significant linear association was found between s-suPAR and age in the donors; thus, all of the s-suPAR levels were adjusted for this age dependency (aa-s-suPAR). The aa-s-suPAR levels were significantly increased in the patients as compared with the donors (P < 0.0001). No difference was found in aa-s-suPAR levels between the lymph node-positive and -negative patients (P = 0.27), and no correlation was seen between aa-s-suPAR and c-suPAR (sigma = 0.08; P = 0.71). During the follow-up period (5.9 years) 77 patients experienced a relapse and 69 died. aa-s-suPAR as a continuous variable was significantly associated with relapse-free survival [hazard ratio (HR), 1.4; 95% confidence interval (CI), 1.1-1.8; P = 0.003] and overall survival (HR, 1.6; 95% CI, 1.2-2.0; P < 0.0001). In multivariate Cox analysis including the classical prognostic parameters in breast cancer, continuous aa-s-suPAR was significantly associated with both relapse-free survival (HR, 1.4; 95% CI, 1.1-1.7; P = 0.001) and overall survival (HR, 1.4; 95% CI, 1.1-1.8; P = 0.002). In these analyses positive lymph nodes, tumor size >2 cm, and negative estrogen receptor content were also significantly associated with patient outcome. CONCLUSION: This study shows that high preoperative aa-s-suPAR levels are significantly associated with poor outcome for breast cancer patients independent of lymph node status, tumor size, and estrogen receptor status.     

Ascites induces modulation of alpha6beta1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48 h. Ascites induced upregulation of alpha6 integrin, without any change in the expression of alphav, beta1 and beta4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression of alpha6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation of alpha6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies against alpha6 and beta1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas.     

High tissue content of urokinase plasminogen activator (u-PA) is associated with high stromal expression of u-PA mRNA in poorly differentiated serous ovarian carcinoma

Urokinase plasminogen activator (u-PA) plays a pivotal role in tissue degradation during tumor spread and metastasis. We have quantitated u-PA in tissue homogenates of 31 serous ovarian tumors and localized u-PA and its mRNA in tissue sections of 26 serous ovarian tumors. The content of u-PA was higher in malignant than in benign tumors, with the highest levels being found in poorly differentiated cancers. In tissue sections, the u-PA mRNA was hybridized with a radiolabeled RNA probe. Signals were almost exclusively found in the epithelium in benign and borderline tumors and in well-differentiated cancers. Poorly differentiated tumors and metastases exhibited prominent stromal expression of u-PA mRNA, whereas epithelial expression was weak or absent. Immuno-histochemical staining co-localized u-PA antigen with its mRNA in the epithelium of benign and borderline tumors and in well-differentiated cancers. Poorly differentiated malignant tumors showed extensive immunostaining in the epithelium in addition to stromal staining. The u-PA mRNA-expressing and u-PA-immunostained cells in the stroma were not tumor cells since no cells in the stroma were positive for cytokeratin. Poorly differentiated tumors had increased numbers of stromal macrophages (CD68), and they co-localized with some of the u-PA-positive cells. The presence of u-PA antigen and the absence of u-PA mRNA in tumor epithelium of poorly differentiated tumors and metastases together with the presence of u-PA mRNA in the stroma suggests production in stromal cells and subsequent binding to receptor sites in tumor cells. Int. J. Cancer (Pred. Oncol.) 79:588–595, 1998. © 1998 Wiley-Liss, Inc.     

TRIB3 protein denotes a good prognosis in breast cancer patients and is associated with hypoxia sensitivity

Background

Tribbles homolog 3 (TRIB3) is a pseudokinase involved in the regulation of several signaling pathways involved in cell survival and/or cell stress. Here, we determined the correlation between breast cancer prognosis and TRIB3 protein levels and established the role of TRIB3 in cell survival after hypoxia and/or radiotherapy.

Material and methods

TRIB3 mRNA and protein were quantified in a new independent breast cancer patient cohort using QPCR and a new specific avian antibody against TRIB3. In addition, we used siRNA-mediated knockdown of TRIB3 in a colony-forming assay after hypoxia and radiotherapy.

Results

TRIB3 mRNA and protein levels did not correlate in breast cancer cell lines or human breast cancer material. We validated our earlier finding that high TRIB3 mRNA denotes a poor prognosis, but found that high TRIB3 protein levels were associated with a good prognosis in breast cancer patients. We also show that knockdown of TRIB3 resulted in an increased survival under hypoxic conditions.

Conclusion

Whereas mRNA levels of TRIB3 are related with a poor prognosis, TRIB3 protein is associated with a good prognosis in human breast cancer patients, possibly due to the fact that TRIB3 is involved in hypoxia tolerance.     

Adiponectin receptor-1 expression is associated with good prognosis in gastric cancer

Background

Adiponectin is inversely related to BMI, positively correlates with insulin sensitivity, and has anti-atherogenic effects. In recent years, adiponectin has been well studied in the field of oncology. Adiponectin has been shown to have antiproliferative effects on gastric cancer, and adiponectin expression is inversely correlated with clinical staging of the disease. However, no studies have reported the correlation between serum adiponectin and receptor expression with disease progression.

Methods

In this study, we evaluated expression levels of 2 adiponectin receptors--AdipoR1 and AdipoR2--and attempted to correlate their expression with prognosis in gastric cancer patients. AdipoR1 and AdipoR2 expression in gastric cancer cell lines (MKN45, TMK-1, NUGC3, and NUGC4) was evaluated by western blotting analysis, and the antiproliferative potential of adiponectin was examined in vitro. Serum adiponectin levels were evaluated in 100 gastric cancer patients, and the expression of AdipoR1 and AdipoR2 was assessed by immunohistochemical staining.

Results

MKN45 and NUGC3 expressed higher levels of AdipoR1 compared to NUGC4, even though there was no significance in AdipoR2 expression. The antiproliferative effect of adiponectin was confirmed in MKN45 and NUGC3 at 10 μg/ml. No significant associations were observed between serum adiponectin levels and clinicopathological characteristics, but lymphatic metastasis and peritoneal dissemination were significantly higher in the negative AdipoR1 immunostaining group (24/32, p = 0.013 and 9/32, p = 0.042, respectively) compared to the positive AdipoR1 group (lymphatic metastasis, 33/68; peritoneal dissemination, 8/68). On the other hand, AdipoR2 expression was only associated with histopathological type (p = 0.001). In survival analysis, the AdipoR1 positive staining group had significantly longer survival rates than the negative staining group (p = 0.01). However, multivariate analysis indicated that AdipoR1 was not an independent prognostic factor on patient's survival on gastric cancer.

Conclusions

In gastric cancer, adiponectin has the possibility to be involved in cell growth suppression via AdipoR1. The presence of AdipoR1 could be a novel anticancer therapeutic target in gastric cancer.

     

The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients

Epithelial ovarian cancer is the leading cause of death among female genital malignancies. Reduced expression of the cell adhesion molecule E-cadherin was previously shown to be associated with adverse prognostic features. The role of the E-cadherin repressor Snail in ovarian cancer progression remains to be elucidated. We analysed formalin-fixed and paraffin-embedded specimens of 48 primary ovarian tumours and corresponding metastases for expression of E-cadherin and Snail by immunohistochemistry. We found a significant correlation between E-cadherin expression in primary cancers and their corresponding metastases (P<0.001). This correlation was found for Snail expression as well (P<0.001). There was a significant (P=0.008) association of reduced E-cadherin expression in primary ovarian cancer with shorter overall survival. Similarly, Snail expression in corresponding metastases (P=0.047) was associated with reduced overall survival of the patients. Additionally, the group of patients showing reduced E-cadherin and increased Snail immunoreactivity in primary tumours and corresponding metastases, respectively, had a significantly higher risk of death (P=0.002 and 0.022, respectively) when compared to the patient group with the reference expression profile E-cadherin positive and Snail negative. Taken together, the results of our study show that the E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients.     

HLA-G expression is associated with metastasis and poor survival in the Balb/c nu/nu murine tumor model with ovarian cancer

Aberrant HLA-G expression is associated with tumor invasiveness and poor clinical prognosis; however, there is a lack of preclinical animal model to address whether HLA-G plays a causal role in the unfavorable prognosis of malignancies. In the current study, ovarian carcinoma cell lines (HO-8910 and Ovcar-3) were transfected with HLA-G gene. HLA-G expression was analyzed with western blot and flow cytometry. Transwell experiment was performed to analyze the cell migration and invasion capability and/or multicellular spheroid formation was investigated with the 3D culture assay in vitro. The effects of HLA-G expression for tumor cell organ metastasis and for mouse survival was analyzed with the Balb/c nu/nu mouse model. Our data showed that HO-8910-G and Ovcar-3-G cells are of higher invasion potential compared with the parental HO-8910 and Ovcar-3 cells. Multicellular spheroid formation exists only in HO-8910-G cells in a 3D culture assay. In Balb/c nu/nu mouse model, widespread metastasis was observed in mice xenografted with HO-8910-G cells, but not in the group with parental cells. Mouse survival was dramatically decreased in HO-8910-G and Ovcar-3-G xenografted mice than that with HO-8910 and Ovcar-3 cells, respectively. In summary, our study provided the first evidence that HLA-G expression is associated with tumor metastasis and with poor survival in an animal model with ovarian cancer.     

Cleaved forms of the urokinase plasminogen activator receptor in plasma have diagnostic potential and predict postoperative survival in patients with ovarian cancer

PURPOSE: To evaluate the plasma level of different forms of soluble urokinase plasminogen activator receptor (suPAR) as discriminators between malignant, borderline, and benign ovarian tumors and as prognostic markers in patients with ovarian cancer. EXPERIMENTAL DESIGN: The different suPAR forms were measured in preoperative plasma samples obtained from 335 patients with adnexal lesions using three different time-resolved fluoresence assays (TR-FIA): TR-FIA 1 measuring intact suPAR, suPAR(I-III), TR-FIA 2 measuring the total amount of suPAR(I-III) and the cleaved form, suPAR(II-III), and TR-FIA 3 measuring the liberated uPAR(I). Tumors were classified as benign (n = 211), borderline (possibly malignant; n = 30), and well (n = 19), moderately (n = 15), and poorly (n = 60) differentiated malignant. RESULTS: All uPAR forms as well as CA125 were statistically significant in univariate analysis discriminating between benign, borderline, and invasive tumors. Restricting the analysis of invasive tumors to early stage (I and II) showed similar results. A combination of CA125 and suPAR(I-III) + suPAR(II-III) discriminated between malignant (all stages) and benign tumors [AUC, 0.94; 95% confidence interval (95% CI), 0.90-0.98] as well as borderline and benign tumors (AUC, 0.78; 95% CI, 0.67-0.89). All suPAR forms were markers for poor prognosis in univariate analyses, and high preoperative plasma level of uPAR(I) is an independent predictor of poor prognosis (hazard ratio, 1.84; 95% CI, 1.15-2.95; P = 0.011) in multivariate analyses including age and CA125. CONCLUSIONS: High concentration of plasma uPAR(I) is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The combination of plasma suPAR(I-III) + suPAR(II-III) and CA125 discriminates between malignant and benign tumors with an AUC of 0.94.     

缺氧和新生血管生成与晚期卵巢浆液性癌腹膜播散及预后相关性的研究

目的:探讨缺氧和新生血管生成在晚期卵巢浆液性癌腹水形成和腹膜播散中的作用,及其与预后的关系。方法:用免疫组织化学方法检测HIF-1α、bFGF和CD34蛋白在72例晚期卵巢浆液性癌患者原发灶、腹水沉渣和腹腔转移灶中的表达,分析上述3种因子与预后的关系。结果:HIF-1α蛋白在晚期卵巢浆液性囊腺癌患者原发灶和转移灶中的高表达率分别为83.3%(60/72)和90.6%(48/53),高于腹水细胞中的61.3%(19/31),差异有统计学意义,P值分别为0.036和0.024;bFGF在晚期卵巢浆液性囊腺癌患者的原发灶、转移灶和腹水细胞中的表达率分别为87.5%(63/72)、100.0%(53/53)和80.6%(25/31),差异无统计学意义。残留病灶(直径>1cm)、HIF-1α、bFGF和MVD表达与晚期卵巢浆液性囊腺癌患者的复发或转移具有明显的正相关,P值分别为0.026、0.009、0.009和0.005。COX模型分析显示,MVD是晚期卵巢浆液性囊腺癌的独立预后因素,P=0.030。结论:HIF-1α和bFGF在卵巢浆液性囊腺癌腹水形成和腹膜转移中有重要作用,MVD是晚期卵巢浆液性囊腺癌的独立预后因素。     

Increased phosphotyrosine in breast cancer tissue is associated with a worse prognosis

Summary We have previously demonstrated that phosphotyrosine can be identified in breast cancer cells using an immunohistochemical stain. We have subsequently used this technique to characterize 106 women with breast cancer (46 with Stage 1 and 60 with Stage 2) who have been followed for at least four years by one oncologist. We analyzed all primary breast cancer tissue using immunohistochemical staining and the amount of phosphotyrosine (PT) was scored on a 0 to 3 range. The PT score of the primary tumor was unrelated to either breast cancer stage or estrogen and progesterone receptor analysis, as high PT scores were noted in both disease stages and all receptor categories. We did find that patients with either no or trace (1+) amounts of PT survived longer than those patients with higher amounts of PT. The patients with low PT had significantly lower chance of relapse (Chi Square = 15.8, p < 0.001) and a lower mortality (Chi Square = 13.1, p = 0.001). We conclude that immunohistochemical methods to determine the PT score may identify patients at higher risk for disease relapse independent of tumor stage or hormonal status.     

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.     

Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer

Plasminogen activator inhibitor (PAI)-1 is predictive of poor outcome in several types of cancer. The present study investigated the biological role for PAI-1 in ovarian cancer and potential of targeted pharmacotherapeutics. In patients with ovarian cancer, PAI-1 mRNA expression in tumor tissues was positively correlated with poor prognosis. To determine the role of PAI-1 in cell proliferation in ovarian cancer, the effects of PAI-1 inhibition were examined in PAI-1-expressing ovarian cancer cells. PAI-1 knockdown by small interfering RNA resulted in significant suppression of cell growth accompanied with G2/M cell cycle arrest and intrinsic apoptosis. Similarly, treatment with the small molecule PAI-1 inhibitor TM5275 effectively blocked cell proliferation of ovarian cancer cells that highly express PAI-1. Together these results suggest that PAI-1 promotes cell growth in ovarian cancer. Interestingly, expression of PAI-1 was increased in ovarian clear cell carcinoma compared with that in serous tumors. Our results suggest that PAI-1 inhibition promotes cell cycle arrest and apoptosis in ovarian cancer and that PAI-1 inhibitors potentially represent a novel class of anti-tumor agents.