Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

Witte, J; Sweep, Fred C.G.J.; Klijn, Jan G.M.; Grebenschikov, N.; Peters, H. A.; Look, Maxime P.; Tienoven, Th H van; Heuvel, J. J. T. M.; Vries, Joan Bolt-de; Benraad, Theo J.; Foekens, John A.

doi:10.1038/sj.bjc.6690353

Cited by 39 publications

(35 citation statements)

References 32 publications

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“…PAI-1 is thought to inhibit activation of tPA or uPA, an event that correlates with poor clinical outcomes in cancer (45,46); however, PAI-1 also serves as an indicator of poor prognosis in breast cancer (47). These findings may be attributed to differences in cell types and experimental models.…”

Section: Discussioncontrasting

confidence: 42%

ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

et al. 2014

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The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease. Cancer Res; 74(18); 5229-43. Ó2014 AACR.

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Section: Discussioncontrasting

confidence: 42%

ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

et al. 2014

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“…Evidently, this finding is a (de Witte et al, 1999a), and for tPA, 2.40 and 13.01 ng mg protein -1 (de Witte et al, 1999b). These biochemical assays are very sensitive and easily can be performed on as little as 25 mg of tissue.…”

Section: Discussionmentioning

confidence: 81%

Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours

et al. 2001

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Summary Using a previously developed enzyme-linked immunosorbent assay (ELISA), the levels of the receptor for urokinase-type plasminogen activator (uPAR) were determined in cytosols and corresponding membrane pellets derived from 878 primary breast tumours. The levels of uPAR in the pellet extracts were more than 3-fold higher than those measured in the cytosols (P < 0.001). Moreover, the uPAR levels in the two types of extracts were weakly, though significantly, correlated with each other (r S = 0.20, P < 0.001). In Cox univariate analysis, high cytosolic levels of uPAR were significantly associated with reduced overall survival (OS) and relapse-free survival (RFS). The levels of uPAR in pellet extracts appeared not to be related with patient survival. In multivariate analysis, elevated levels of uPAR measured in cytosols and pellet extracts were found to be independent predictors of poor OS, not RFS. The prediction of poor prognosis on the basis of high uPAR levels emphasizes its important role in plasmin-mediated degradation of extracellular matrix proteins during cancer invasion and metastasis.

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“…The complex selectively reflects the amount of uPA that has been activated from proenzyme uPA and subsequently inactivated by PAI-1. We have earlier shown that the complex of tissue-type plasminogen activator:PAI-1 as measured in the soluble, nonmembrane bound fraction has significant clinical relevance in terms of RFS and OS, whereas levels in pelleted (membrane) fractions were substantially less relevant (17). Furthermore, the levels of uPA and PAI-1 in the pellet extracts provided less prognostic information as compared with those in the soluble, nonmembrane bound extracts (30).…”

Section: Discussionmentioning

confidence: 94%

“…Therefore, it can be hypothesized that the tumor levels of uPA:PAI-1 complex may provide valuable predictive information in patients with primary breast cancer. In the current study we focused on the clinical relevance of the complex in the soluble, nonmembrane bound fraction, because in an earlier study it was shown that the complex of tissue-type plasminogen activator:PAI-1 as measured in the soluble fraction has clinical relevance in terms of relapse-free survival (RFS) and overall survival (OS), whereas levels in pelleted (membrane) fractions were substantially less relevant (17).…”

Section: Introductionmentioning

confidence: 99%

Predictive Impact of Urokinase-Type Plasminogen Activator

Manders

Tjan‐Heijnen

Span³

et al. 2004

Cancer Research

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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.

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Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

Cited by 39 publications

References 32 publications

ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours

Predictive Impact of Urokinase-Type Plasminogen Activator

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