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Clinical Investigations |
Division of Endocrine Oncology, Department of Medical Oncology [J. A. F., H. A. P., M. P. L., H. P., M. E. M-v. G., J. G. M. K.], and Departments of Statistics [W. L. J. v. P.] and Pathology [S. C. H-L.], Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/Academic Hospital, NL-3075 Rotterdam, the Netherlands; the Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, D-81675 München, Germany [M. S.]; Institut für Immunologie und Serologie der Universität, D-69120 Heidelberg, Germany [M. D. K.]; Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen, Denmark [N. B.]; and Frauenklinik und Poliklinik, Universitäts-Krankenhaus der Universität Hamburg, D-20246 Hamburg, Germany [F. J.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Duffy et al. (15) were the first to link increased levels of uPA activity in breast tumor extracts with a high rate of relapse in patients with breast cancer. This important finding of an association between uPA and a poor prognosis has been confirmed by various research groups measuring uPA antigen levels (16) in breast tumors, as well as in a variety of other cancer types (reviewed in Refs. 4 , 17 ). Interestingly, immunocytologically detected uPA-positive tumor cells in bone marrow from primary breast cancer patients were predictive of a poor prognosis (18) . Moreover, as reported by Jänicke et al. (19) , surprisingly at first, increased levels of the inhibitor PAI-1 were associated with a poor prognosis in primary breast cancer (4 , 17) , and like uPA, also in recurrent breast cancer treated with tamoxifen (20) . These findings can now partly be explained by the recently ascribed role of PAI-1 in tumor cell adhesion and migration (1, 2, 3) . As would be expected, high tumor levels of uPAR were associated with a poor prognosis (21 , 22) , and high levels of PAI-2 were associated with a favorable prognosis in patients with breast cancer (23 , 24) .
Because simultaneous measurement of the different components of the uPA system of plasminogen activation may provide more powerful prognostic information, we determined the levels of uPA, uPAR, PAI-1, and PAI-2 in breast tumors of 2780 patients and have correlated their levels with RFS and OS.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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uPA, uPAR, PAI-1, and PAI-2 levels were determined in breast tumor cytosols with ELISAs. For uPA and PAI-1, ELISA (27 , 28) reagents have been used that are commercially available in assay kits (American Diagnostica, Greenwich, CT). The details of the assay procedures, including those of the specificity and performance of the uPAR and PAI-2 ELISAs, have been described elsewhere (22 , 24 , 29) . To enable the assessment of the between-assay variations (% CV), in each assay-run an aliquot of a pooled breast cancer cytosol sample was analyzed. The between-assay CV was 12.7, 21.2, 14.3, and 8.4% for the uPA, uPAR, PAI-1, and PAI-2 assays, respectively. The within-assay CVs of samples measured in duplicate were all <5%. During the period of the assays (>3 years), there was no significant change in the levels of any of the four factors in the breast cancer cytosol pool. These results suggest that the factors were stable during long-term storage of the cytosols.
Statistics.
The strength of the associations between uPA, uPAR, PAI-1, and PAI-2
was tested with Spearman rank correlation
(rs). The associations of these
factors with other variables were tested with the nonparametric
Wilcoxon Rank-Sum test or Kruskal-Wallis test, followed by a
Wilcoxon-type test for trend across ordered groups where appropriate.
RFS and OS probabilities were calculated by the actuarial method of
Kaplan and Meier (30)
. In our search for the best
categorization of uPA, uPAR, and PAI-1, we have used IRA using RFS as
end point (28
, 31)
. After it had been established that in
a test for trend using log-transformed variables increasing levels were
significantly associated with RFS, an IRA was performed after
correction for age/menopausal status, tumor size and grade, lymph node
status, adjuvant therapy, and ER and PgR status. These factors defined
the basic multivariate model for all patients that we incorporated in
our analyses. Increasing PAI-2 levels were significantly associated
with a favorable prognosis, however, only when uPA was also added to
the basic multivariate model. For node-positive patients, nodal status
was included as N>3 versus N1–3, and for node-negative
patients, nodal status and adjuvant therapy were not applicable. The
univariate and multivariate analyses, including tests for interactions,
were performed using the Cox proportional hazards model
(32)
. The assumption of proportional hazards was verified
graphically. The associated likelihood ratio test was used to test for
differences between models with variables included and excluded. In the
multivariate analyses, the missing values for ER
(n = 76), PgR (n = 120), and tumor grade (n = 677) were treated
as separate groups to allow inclusion of all patients in all models.
The results from Cox analyses, including the basic model and the
components of the uPA system that significantly added to the model,
were used to classify patients into risk groups using as cut points the
10, 25, 50, 75, and 90 percentiles of the calculated linear score from
the Cox analyses. The resulting risk groups are visualized by
Kaplan-Meier curves. All computations were done with the STATA
statistical package, release 6.0 (STATA Corp., College Station, TX).
All Ps are two-sided and relate to all available data during
the total period of follow-up.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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are comparable
with those obtained previously in fewer patients, with reported median
levels in ng/mg of protein of 0.7 for uPA (27)
, 0.87 for
uPAR (22)
, 15.2 for PAI-1 (28)
, and 2.26 for
PAI-2 (24)
. For all four variables, the distribution was
approximately log normal.
The Spearman rank correlation coefficients
(rs) between the various factors of
the uPA system varied from rs = 0.32 (between PAI-2 and PAI-1 or uPAR) to
rs = 0.59 (between uPA and
PAI-1). Table 1
shows their relationships with patient and tumor
characteristics. Levels of all four parameters were higher in ER- or
PgR-negative tumors as compared with hormone receptor-positive tumors.
The levels of uPA were not significantly related with age, menopausal
status, or lymph node status. Well-differentiated and
T3/4 tumors had the lowest uPA levels, whereas
moderately differentiated and T2 tumors had the
highest levels. In general, uPAR followed the same pattern of
distribution over the various patient groups, and all of the
relationships were statistically significant, i.e., the
negative relationships of uPAR with age and menopausal status, and the
positive associations between uPAR and tumor size and nodal status
(Table 1)
. As was also observed for uPA, the highest uPAR and PAI-2
levels were found in moderately differentiated tumors. PAI-1 showed a
positive relationship with tumor size, nodal status, tumor grade, age,
and menopausal status. PAI-2 showed positive relationships with age and
menopausal status, and negative relationships with nodal status and
tumor size (Table 1)
.
Multivariate Analysis.
To study which factors of the urokinase system add significantly to the
prognostic information already provided by traditional prognostic
factors, we first designed a basic multivariate model for all patients
(Table 2)
. This model, which included age, menopausal status, tumor size and
grade, the number of positive lymph nodes, adjuvant therapy, and ER/PgR
status, was significantly associated with RFS
(
2 = 517; df = 15;
P < 0.0001) and OS
(2 = 519; df = 15;
P < 0.0001). For both uPAR and PAI-2, the
results of the IRA, after correction for the basic multivariate model,
suggested that these variables could be considered as categorical
variables with two cut points. The cut points chosen were 0.57 and 1.13
ng/mg of protein for uPAR and 0.62 and 4.05 ng/mg of protein for PAI-2.
On the other hand, for uPA and PAI-1 the results were less clear and
did not reveal a clear indication for cut points. However, to enable
visualization of their relationships with RFS and for reasons of
uniformity with the analyses of uPAR and PAI-2, we categorized uPA and
PAI-1 at the levels of the two largest steps in the IRA. These levels
were 0.19 and 1.21 ng/mg protein for uPA and 9.33 and 45.28 ng/mg
protein for PAI-1. When each variable was added separately to the basic
model for RFS, the addition of uPA resulted in a
2 of 73.6 (df = 2), a
2 of 19.9 (df = 2) for uPAR,
a 2 of 81.4 (df = 2) for
PAI-1, and a 2 of 4.6 (df = 2) for PAI-2. The RHRs and their 95% CI from the Cox multivariate
analysis are listed in Table 2
. High levels of uPA, uPAR, or PAI-1 were
significantly associated with an early relapse, whereas PAI-2 did not
significantly contribute to the basic multivariate model. Similar
results were obtained in the analyses for OS (Table 2)
. The
Kaplan-Meier curves for RFS as a function of the levels of uPA, uPAR,
PAI-1, and PAI-2 are shown in Fig. 1
. There were no statistically significant interactions between any of
the prognostic variables in multivariate analysis for RFS or OS.
Separate Cox multivariate analyses for RFS and OS were subsequently
performed to establish whether combinations of uPA, uPAR, PAI-1, and
PAI-2 would increase the prognostic strength of the classical
prognostic factors already included in the basic model. When the four
factors of the uPA system were added as log-transformed continuous
variables to the basic model for RFS in all patients, high levels of
uPA and PAI-1 were associated with a poor prognosis, whereas high
levels of PAI-2 were associated with a favorable prognosis in the final
model for RFS (for all, P < 0.001). The RHRs
and 95% CIs for the components of the uPA system that are included as
categorical variables in the final model for all patients and in
subgroups of node-negative and node-positive patients are shown in
Table 3
. uPAR did not contribute to any of the models. Only in the analysis for
OS in node-positive patients did PAI-2 not appear to be an independent
prognostic variable. In all other analyses, uPA, PAI-1, and PAI-2
significantly added to the prognostic strength provided by the
classical prognostic factors included in the basic model (Table 3)
. The
increase in 2 caused by the addition of uPA,
PAI-1, and PAI-2 to the basic model was 136 (df = 6) in
the analysis for RFS and 120 in the analysis for OS. In node-negative
patients with a 2 of 76 (df = 12) for the model including age and menopausal status, tumor size and
grade, and ER/PgR status, the 2 as a result
of the addition of uPA, PAI-1, and PAI-2 was 71 (df = 6)
in analysis for RFS, and in the analysis for OS, the
2 increased from 82 to 133 by the addition of
the three factors. In node-positive patients, the
2 increased from 221 (df = 14)
for the model including age and menopausal status, tumor size and
grade, the number of positive lymph nodes, adjuvant therapy, and ER/PgR
status to 295 in the analysis for RFS, and from 207 to 297 in the
analysis for OS.
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and 61% in analysis for OS (Fig. 2B)
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respectively. For node-negative
patients, at 10 years the difference between the 10% lowest risk group
(86 ± 4% relapse free) and the 10% highest risk group
(27 ± 6% relapse free) was 59%. For node-positive
patients, at 10 years the difference in RFS between the two extreme
groups was 52% (61 ± 6% and 9 ± 3%
for the 10% lowest and highest risk groups, respectively).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunohistochemistry and in situ hybridization on breast cancer tissues showed that uPA, uPAR, PAI-1, and/or PAI-2 are expressed and synthesized by both tumor cells and host cells, including (myo)fibroblasts, endothelial cells, and phagocytic cells (reviewed in Refs. 1 and 4 ). A differential expression of the four components by the various cell types and an interplay between these cells may be necessary for the function of the system in various cellular processes at different stages of tumor progression (1) . It has been shown that, in general, elevated antigen levels of uPA, uPAR, and PAI-1 determined in tumor extracts are associated with poor prognosis in a variety of cancer types. In contrast, increased PAI-2 antigen levels are associated with a favorable prognosis (reviewed in Refs. 1 , 4, and 17 ). The association of a high tumor level of PAI-1 with a poor prognosis in patients with primary breast cancer (19) has been explained by its inhibition of uPA activity and thus preventing degradation of tumor stroma, allowing new ECM to be formed (33) , but it can also be attributed to its recently ascribed role in tumor cell adhesion and migration (10 , 11 , 13 , 14) . Furthermore, PAI-1 has been shown to be involved in uPAR clearance from the cell surface by promoting internalization of the formed ternary uPA:uPAR:PAI-1 complex (3 , 34) . Besides its antiproteolytic function, PAI-1 is necessary for focalized and optimal invasiveness (35) , associated with angiogenic activity (36) , and is essential for tumor cell invasion and tumor vascularization in PAI-1-deficient mice (37) . Together these observations strongly imply that PAI-1 plays a primary role in tumor progression. Because we showed previously that the uPAR level in the cytosol was a much stronger prognostic factor than the uPAR level in the detergent extract, which also contains plasma membrane components (22) , uPAR was measured only in the cytosols in the present study. The higher prognostic value of uPAR in cytosols was explained by its presentation as a water-soluble degradation product that has lost its lipid anchor because of the action of either proteases or phospholipases. The soluble uPAR may have been formed as a result of plasmin generation, which on cell surfaces happens in close vicinity to uPAR (38) . Such a soluble form of uPAR has been detected in ascites fluid from patients with ovarian cancer (39) . It was also found to be elevated in the blood of cancer patients (40 , 41) and patients with paroxysmal nocturnal hemoglobinuria (42) , when compared with healthy controls. Recently, high plasma levels of soluble uPAR were found to be correlated with a poor prognosis in patients with colorectal cancer (43) .
We showed that the interrelationships between uPA, uPAR, PAI-1, and
PAI-2 were all positive and statistically significant, with Spearman
correlations ranging from 0.32 to 0.59. Similar positive relationships
between two or more of these factors have been reported before
(21, 22
, 24
, 28
, 44, 45, 46)
. In the present study, all four
variables were negatively related with ER and PgR. The levels of uPA
were in general not significantly related with poor prognostic
characteristics. However, the levels of uPAR and PAI-1 were in most
analyses weakly, although significantly, associated with poor
prognostic features, whereas PAI-2 levels were associated with
favorable prognostic characteristics. Because most relationships were
weak yet statistically significant, probably as a result of the large
numbers included, several of the observed associations may hardly be of
biological relevance. With respect to prognosis, we show that high
tumor levels of uPA, uPAR, and PAI-1 were associated with poor, and of
PAI-2 with a favorable, RFS and OS for patients with primary breast
cancer. Moreover, when added separately to the basic multivariate model
including traditional prognostic factors, uPA, uPAR, and PAI-1 all gave
additional prognostic information. PAI-1 appeared to be the second
strongest prognostic factor after nodal status, superior to the
established factors such as tumor size (Table 2)
. In contrast, PAI-2
levels were not significantly associated with prognosis in multivariate
analysis when corrected for the contribution of traditional prognostic
factors. PAI-2 was significantly associated with a favorable prognosis
when added to the multivariate models together with uPA and PAI-1. This
may seem odd, however, we have shown before that PAI-2 was only of
prognostic value in tumors with high levels of uPA and not in those
with low uPA levels (24)
. This phenomenon of PAI-2 being
an independent favorable prognostic factor in the presence of uPA could
be attributable to the positive association between the levels of PAI-2
and the other three components of the uPA system that are related to a
poor prognosis. When combining the various factors of the urokinase
system in multivariate analyses for RFS and OS, uPAR did not further
contribute to the models in which uPA and/or PAI-1 were included.
It has been argued recently by Powles (47)
that "the
time has come to individualize adjuvant chemotherapy, basing it more on
the biological characteristics of individual tumors rather than on the
widespread treatment of large groups of patients." In this line of
thought, we aimed to establish a prognostic score based on the
contribution of various traditional and tumor cell biological
prognostic factors. Using a score based on the traditional prognostic
variables and the independent biological variables uPA, PAI-1, and
PAI-2, we were able to obtain survival curves that showed a wide
separation between patients in the various risk groups of patients, as
well as in nodal subgroups of patients. It should, however, be
emphasized that the largest power of the models in all patients are
derived from the classical prognostic factors, particularly nodal
status and tumor size. In analysis for RFS in all patients, the
2 of the basic model containing the classical
prognostic factors was 517 (df = 15). The independent
biological factors uPA, PAI-1, and PAI-2 only added moderately to this
model (increase in 2 of 136, df = 6). Importantly, for node-negative patients, this increase in
2 caused by the addition of the three factors
was 71 (df = 6). This is relatively high compared with
the 2 of 76 (df = 12) already
provided by the classical prognostic factors.
In the present study, the levels of the components of the urokinase system of plasminogen activation were determined with specific ELISAs performed on tumor extracts, which does not discriminate between the cell type that expresses the specific factor. Nevertheless, the measured levels correlated with prognosis in several cancer types in many published studies. An advantage of using ELISAs is that the assays can easily be subjected to external quality control programs (48) . With respect to immunohistochemical assessment of the components of the uPA system, discrepant results on the localization of the different factors have been published by various groups. It has been argued by Andreasen et al. (1) that to ascertain the specificity of immunohistochemical stainings and to obtain conclusive results, special care should be taken regarding a number of control experiments and that, although immunohistochemical studies may reveal where the various components are present, the localization of the active components remains elusive (1) .
Several of the components of the uPA system are potential targets for antiangiogenic, anti-invasive, and/or antimetastatic therapy, and various different approaches to interfere with the expression or reactivity of uPA or uPAR at the gene or protein level have been proven successful. Such therapeutic approaches include the application of antisense oligonucleotides, antibodies, enzyme inhibitors, and recombinant and synthetic uPA and uPAR analogues (reviewed in Refs. 1 , 3, and 4 ). Because the uPA system plays an important role in tumor cell adhesion and migration as well, treatments aimed at interfering with the nonproteolytic properties of this multifactorial system may also prove beneficial.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grant DDHK 96-1234 of the Dutch
Cancer Society, Amsterdam, the Netherlands. 
2 To whom requests for reprints should be
addressed, at Josephine Nefkens Institute, Dr. Molewaterplein 50, Room
Be426, 3015 GE Rotterdam, the Netherlands. Phone: (31)-10-4088 369;
Fax: (31)-10-4088-377/365; E-mail: foekens{at}bidh.azr.nl
3 The abbreviations used are: ECM, extracellular
matrix; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor;
PAI, plasminogen activator inhibitor; RFS, relapse-free survival; OS,
overall survival; RHR, relative hazard rates; CI, confidence interval;
df, degrees of freedom; 2, increase in
2; CV, coefficient of variation; ER, estrogen receptor;
PgR, progesterone receptor; IRA, isotonic regression analysis.
Received 7/ 8/99. Accepted 12/ 2/99.
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N. Harbeck, R. E. Kates, M. P. Look, M. E. Meijer-van Gelder, J. G. M. Klijn, A. Kruger, M. Kiechle, F. Janicke, M. Schmitt, and J. A. Foekens Enhanced Benefit from Adjuvant Chemotherapy in Breast Cancer Patients Classified High-Risk according to Urokinase-type Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor Type 1 (n = 3424) Cancer Res., August 15, 2002; 62(16): 4617 - 4622. [Abstract] [Full Text] [PDF]
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 R. Castello, A. Estelles, C. Vazquez, C. Falco, F. Espana, S. M. Almenar, C. Fuster, and J. Aznar Quantitative Real-Time Reverse Transcription-PCR Assay for Urokinase Plasminogen Activator, Plasminogen Activator Inhibitor Type 1, and Tissue Metalloproteinase Inhibitor Type 1 Gene Expressions in Primary Breast Cancer Clin. Chem., August 1, 2002; 48(8): 1288 - 1295. [Abstract] [Full Text] [PDF]
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 D.P. Dickinson CYSTEINE PEPTIDASES OF MAMMALS: THEIR BIOLOGICAL ROLES AND POTENTIAL EFFECTS IN THE ORAL CAVITY AND OTHER TISSUES IN HEALTH AND DISEASE Critical Reviews in Oral Biology & Medicine, May 1, 2002; 13(3): 238 - 275. [Abstract] [Full Text] [PDF]
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R. Riisbro, I. J. Christensen, T. Piironen, M. Greenall, B. Larsen, R. W. Stephens, C. Han, G. Hoyer-Hansen, K. Smith, N. Brunner, et al. Prognostic Significance of Soluble Urokinase Plasminogen Activator Receptor in Serum and Cytosol of Tumor Tissue from Patients with Primary Breast Cancer Clin. Cancer Res., May 1, 2002; 8(5): 1132 - 1141. [Abstract] [Full Text] [PDF]
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 B. R. Binder, G. Christ, F. Gruber, N. Grubic, P. Hufnagl, M. Krebs, J. Mihaly, and G. W. Prager Plasminogen Activator Inhibitor 1: Physiological and Pathophysiological Roles Physiology, April 1, 2002; 17(2): 56 - 61. [Abstract] [Full Text] [PDF]
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J. Sturge, J. Hamelin, and G. E. Jones N-WASP activation by a {beta}1-integrin-dependent mechanism supports PI3K-independent chemotaxis stimulated by urokinase-type plasminogen activator J. Cell Sci., February 15, 2002; 115(4): 699 - 711. [Abstract] [Full Text] [PDF]
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L. DEVY, S. BLACHER, C. GRIGNET-DEBRUS, K. BAJOU, V. MASSON, R. D. GERARD, A. GILS, G. CARMELIET, P. CARMELIET, P. J. DECLERCK, et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent FASEB J, February 1, 2002; 16(2): 147 - 154. [Abstract] [Full Text] [PDF]
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 M. P. Look, W. L. J. van Putten, M. J. Duffy, N. Harbeck, I. J. Christensen, C. Thomssen, R. Kates, F. Spyratos, M. Ferno, S. Eppenberger-Castori, et al. Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients J Natl Cancer Inst, January 16, 2002; 94(2): 116 - 128. [Abstract] [Full Text] [PDF]
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J. Chen, C. Baskerville, Q. Han, Z. K. Pan, and S. Huang alpha v Integrin, p38 Mitogen-activated Protein Kinase, and Urokinase Plasminogen Activator Are Functionally Linked in Invasive Breast Cancer Cells J. Biol. Chem., December 14, 2001; 276(51): 47901 - 47905. [Abstract] [Full Text] [PDF]
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L. Rosano, M. Varmi, D. Salani, V. Di Castro, F. Spinella, P. Giorgio Natali, and A. Bagnato Endothelin-1 Induces Tumor Proteinase Activation and Invasiveness of Ovarian Carcinoma Cells Cancer Res., November 1, 2001; 61(22): 8340 - 8346. [Abstract] [Full Text] [PDF]
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N. Harbeck, U. Alt, U. Berger, A. Kruger, C. Thomssen, F. Janicke, H. Hofler, R. E. Kates, and M. Schmitt Prognostic Impact of Proteolytic Factors (Urokinase-Type Plasminogen Activator, Plasminogen Activator Inhibitor 1, and Cathepsins B, D, and L) in Primary Breast Cancer Reflects Effects of Adjuvant Systemic Therapy Clin. Cancer Res., September 1, 2001; 7(9): 2757 - 2764. [Abstract] [Full Text] [PDF]
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V. C. L. Lin, A. S. Eng, N. E. Hen, E. H. L. Ng, and S. H. Chowdhury Effect of Progesterone on the Invasive Properties and Tumor Growth of Progesterone Receptor-transfected Breast Cancer Cells MDA-MB-231 Clin. Cancer Res., September 1, 2001; 7(9): 2880 - 2886. [Abstract] [Full Text] [PDF]
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G. Konecny, M. Untch, J. Arboleda, C. Wilson, S. Kahlert, B. Boettcher, M. Felber, M. Beryt, S. Lude, H. Hepp, et al. HER-2/neu and Urokinase-Type Plasminogen Activator and Its Inhibitor in Breast Cancer Clin. Cancer Res., August 1, 2001; 7(8): 2448 - 2457. [Abstract] [Full Text] [PDF]
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C. Isogai, W. E. Laug, H. Shimada, P. J. Declerck, M. F. Stins, D. L. Durden, A. Erdreich-Epstein, and Y. A. DeClerck Plasminogen Activator Inhibitor-1 Promotes Angiogenesis by Stimulating Endothelial Cell Migration toward Fibronectin Cancer Res., July 1, 2001; 61(14): 5587 - 5594. [Abstract] [Full Text] [PDF]
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P. O. Chappuis, B. Dieterich, V. Sciretta, C. Lohse, H. Bonnefoi, S. Remadi, and A.-P. Sappino Functional Evaluation of Plasmin Formation in Primary Breast Cancer J. Clin. Oncol., May 15, 2001; 19(10): 2731 - 2738. [Abstract] [Full Text] [PDF]
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L. S. Gutierrez, A. Schulman, T. Brito-Robinson, F. Noria, V. A. Ploplis, and F. J. Castellino Tumor Development Is Retarded in Mice Lacking the Gene for Urokinase-Type Plasminogen Activator or Its Inhibitor, Plasminogen Activator Inhibitor-1 Cancer Res., October 1, 2000; 60(20): 5839 - 5847. [Abstract] [Full Text]
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B. Muehlenweg, I. Assfalg-Machleidt, S. G. Parrado, M. Burgle, S. Creutzburg, M. Schmitt, E. A. Auerswald, W. Machleidt, and V. Magdolen A Novel Type of Bifunctional Inhibitor Directed against Proteolytic Activity and Receptor/Ligand Interaction. CYSTATIN WITH A UROKINASE RECEPTOR BINDING SITE J. Biol. Chem., October 20, 2000; 275(43): 33562 - 33566. [Abstract] [Full Text] [PDF]
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0.19 ng/mg of protein, >1.21
ng/mg of protein versus 