Urokinase plasminogen activator: A prognostic marker in multiple types of cancer

Duffy, Michael J.; Maguire, Teresa; McDermott, Enda; O’Higgins, N.

doi:10.1002/(sici)1096-9098(199906)71:2<130::aid-jso14>3.0.co;2-9

Cited by 161 publications

(112 citation statements)

References 43 publications

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“…A clinical usefulness of these systems to predict the outcome in breast cancer patients has been expected. Numerous studies have established a prognostic value of the levels of uPA and PAI-1 and of angiogenesis in breast cancer patients (Fox, 1997;Harbeck et al, 1998;Duffy et al, 1999;Look and Foekens, 1999;Look et al, 2002). However, none of these factors are yet used in current clinical practice.…”

Section: Discussionmentioning

confidence: 99%

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Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

et al. 2003

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Tumour angiogenesis and the levels of plasminogen activator inhibitor type 1 (PAI-1) are both informative prognostic markers in breast cancer. In cell cultures and in animal model systems, PAI-1 has a proangiogenic effect. To evaluate the interrelationship of angiogenesis and the PAI-1 level in breast cancer, we have evaluated the prognostic value of those factors in a total of 228 patients with primary, unilateral, invasive breast cancer, evaluated at a median follow-up time of 12 years. Microvessels were immunohistochemically stained by antibodies against CD34 and quantitated by the Chalkley counting technique. The levels of PAI-1 and its target proteinase uPA in tumour extracts were analysed by ELISA. The Chalkley count was not correlated with the levels of uPA or PAI-1. High values of uPA, PAI-1, and Chalkley count were all significantly correlated with a shorter recurrence-free survival and overall survival. In the multivariate analysis, the uPA level did not show independent prognostic impact for any of the analysed end points. In contrast, the risk of recurrence was independently and significantly predicted by both the PAI-1 level and the Chalkley count, with a hazard ratio (95% CI) of 1.6 (1.01-2.69) and 1.4 (1.02-1.81), respectively. For overall survival, the Chalkley count, but not PAI-1, was of significant independent prognostic value. The risk of death was 1.7 (1.30-2.15) for Chalkley counts in the upper tertile compared to the lower one. We conclude that the PAI-1 level and the Chalkley count are independent prognostic markers for recurrence-free survival in patients with primary breast cancer, suggesting that the prognostic impact of PAI-1 is not only based on its involvement in angiogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Thus, the level of PAI-1 in primary tumours is one of the most informative biochemical prognostic markers in several cancer types (Duffy, 1996;Harbeck et al, 1998;Knoop et al, 1998;Duffy et al, 1999;Look and Foekens, 1999;Janicke et al, 2001;Look et al, 2002).…”

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confidence: 99%

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

et al. 2003

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“…Overexpression of the components of the plasminogen activation cascade such as urokinase plasminogen activator (uPA) are associated with a poor prognosis and a short disease-free period in patients suffering from breast cancer (reviewed in Duffy et al, 1999;Schmitt et al, 2000). Studies of the plasminogen activation cascade using human breast cancer cell lines have revealed insights into this cascade.…”

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confidence: 99%

The topology of plasminogen binding and activation on the surface of human breast cancer cells

Andronicos

Ranson

2001

Br J Cancer

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SummaryThe urokinase-dependent activation of plasminogen by breast cancer cells plays an important role in metastasis. We have previously shown that the metastatic breast cancer cell line MDA-MB-231 over-expresses urokinase and binds and efficiently activates plasminogen at the cell surface compared to non-metastatic cells. The aim of this study was to further characterise plasminogen binding and determine the topology of cell surface-bound plasminogen in terms of its potential for activation. The lysine-dependent binding of plasminogen at 4˚C to MDA-MB-231 cells was stable and resulted in an activation-susceptible conformation of plasminogen. Topologically, a fraction of bound plasminogen was co-localised with urokinase on the surfaces of MDA-MB-231 cells where it could be activated to plasmin. At 37˚C plasmin was rapidly lost from the cell surface. Apart from actin, other candidate plasminogen receptors were either not expressed or did not co-localise with plasminogen at the cell surface. Thus, based on co-localisation with urokinase, plasminogen binding is partitioned into two functional pools on the surface of MDA-MB-231 cells. In conclusion, these results shed further light on the functional organisation of the plasminogen activation cascade on the surface of a metastatic cancer cell.

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“…In numerous individual trials (reviewed [5][6][7][8]), in our own preliminary work [9][10][11], as well as in a pooled analysis of 8,377 breast cancer patients from 18 different data sets [12] uPA and PAI-1 uniformly showed independent prognostic value. Most of the patients included in these early studies did not receive any chemotherapy, while endocrine therapy was performed in a majority of hormonal receptor positive patients.…”

Section: Introductionmentioning

confidence: 85%

High levels of uPA and PAI-1 predict a good response to anthracyclines

Borštnar

Sadikov

Možina

et al. 2009

Breast Cancer Res Treat

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Urokinase plasminogen activator: A prognostic marker in multiple types of cancer

Cited by 161 publications

References 43 publications

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

The topology of plasminogen binding and activation on the surface of human breast cancer cells

High levels of uPA and PAI-1 predict a good response to anthracyclines

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