Metabolism of tumour-derived urokinase receptor and receptor fragments in cancer patients and xenografted mice

2004 ◽  
Vol 91 (02) ◽  
pp. 403-411 ◽  
Author(s):  
Maria Santovito ◽  
Thomas Frandsen ◽  
Giovanni Aletti ◽  
Augusto Ferrari ◽  
Andrea Lissoni ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Biological Activities ◽  
Tumour Tissue ◽  
Molecular Forms ◽  
Soluble Form ◽  
Mouse Serum ◽  
Tissue Remodelling ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
A Cell

SummaryThe urokinase-type plasminogen activator receptor (uPAR) is involved in cell migration and tissue remodelling, as a receptor for pro-uPA, as a cell adhesion component, and in a soluble form as a chemoattractant. We have analyzed the presence and the molecular forms of uPAR and uPAR-fragments in urine of ovarian cancer patients in comparison with tumour tissue, ascites, and serum. Carcinoma tissue contained high levels of uPAR, but more abundantly the D2D3-fragment. Ascitic fluid contained similar ratio’s of suPAR fragments as corresponding tumour tissue, but serum only contained intact suPAR. Interestingly, urine contained predominantly the uPAR-fragments D1 and D2D3, and the pattern of these fragments was different in cancer patients as compared to healthy individuals. To confirm the hypothesis that circulating and urinary suPAR and suPAR-fragments originate from the tumour tissue, the presence of human suPAR (fragments) was analyzed in mice xenografted with human tumours. Indeed, high levels of urinary D1 fragment were found in mice carrying a tumour displaying cleaved uPAR on the cell surface, but little or no D1 was found in the urine from mice carrying a tumour with full-length uPAR. Mouse serum contained only intact suPAR. Our data demonstrate that the enhanced levels of suPAR fragments in the urine of cancer patients is likely to originate from uPAR expressed in the tumour tissue. Considering the biological activities that uPAR fragments display, the level and typing of uPAR fragments in urine might therefore be clinically more relevant than the plain serum uPAR content.

scholarly journals Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2999
Author(s):  
Benjamin J. Buckley ◽  
Ashna Kumar ◽  
Ashraf Aboelela ◽  
Richard S. Bujaroski ◽  
Xiuju Li ◽  
...  
Keyword(s):  
Selectivity Ratio ◽  
Dual Targeting ◽  
Sodium Hydrogen ◽  
Type Plasminogen Activator ◽  
Single Target ◽  
Urokinase Type Plasminogen Activator ◽  
Anti Cancer ◽  
Sodium Hydrogen Exchanger ◽  
A Cell ◽  
Cell Invasiveness

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice

2011 ◽  
Vol 105 (05) ◽  
pp. 892-900 ◽  
Author(s):  
Naoyuki Kawao ◽  
Nobuo Nagai ◽  
Yukinori Tamura ◽  
Kiyotaka Okada ◽  
Masato Yano ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Inflammatory Marker ◽  
Phenotypic Heterogeneity ◽  
Border Region ◽  
Tissue Type ◽  
Tissue Remodelling ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Liver Repair ◽  
Deficient Mice

SummaryUrokinase-type plasminogen activator (u-PA) plays an important role in tissue remodelling through the activation of plasminogen in the liver, but its mechanisms are less well known. Here, we investigated the involvement of u-PA in the accumulation and phenotypic heterogeneity of macrophages at the damaged site during liver repair. After induction of liver injury by photochemical reaction in mice, the subsequent pathological responses and expression of phenotypic markers in activated macrophages were analysed histologically. Fibrinolytic activity at the damaged site was also examined by fibrin zymography. In wild-type mice, the extent of damage decreased gradually until day 14 and was associated with an accumulation of macrophages at the border of the damaged site. In addition, the macrophages that accumulated near the damaged tissue expressed CD206, a marker of highly phagocytic macrophages, on day 7. Further, macrophages that were adjacent to CD206-positive cells expressed inducible nitric oxide synthase (iNOS), a pro-inflammatory marker. u-PA activity increased at the damaged site on days 4 and 7, which distributed primarily at the border region. In contrast, in u-PA-deficient mice, the decrease in damage size and the accumulation of macrophages were impaired. Further, neither CD206 nor iNOS was expressed in the macrophages that accumulated at the border region in u-PA-deficient mice. Mice deficient for the gene encoding either u-PA receptor (u-PAR) or tissue-type plasminogen activator experienced normal recovery during liver repair. These data indicate that u-PA mediates the accumulation of macrophages and their phenotypic heterogeneity at the border of damaged sites through u-PAR-independent mechanisms.

scholarly journals Soluble Urokinase Receptors in Focal Segmental Glomerulosclerosis: A Review on the Scientific Point of View

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Andreas Kronbichler ◽  
Moin A. Saleem ◽  
Björn Meijers ◽  
Jae Il Shin
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Point Of View ◽  
Soluble Form ◽  
Glomerular Diseases ◽  
Segmental Glomerulosclerosis ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
End Stage

Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerular disorders in both children and adults which can progress to end-stage renal failure. Although there are genetic and secondary causes, circulating factors have also been regarded as an important factor in the pathogenesis of FSGS, because about 40% of the patients with FSGS have recurrence after renal transplantation. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of uPAR, which is a membrane-bound protein linked to GPI in various immunologically active cells, including podocytes. It has recently been suggested as a potential circulating factor in FSGS by in vitro podocyte experiments, in vivo mice models, and human studies. However, there have also been controversies on this issue, because subsequent studies showed conflicting results. suPAR levels were also increased in patients with other glomerular diseases and were inversely correlated with estimated glomerular filtration rate. Nevertheless, there has been no balanced review on this issue. In this review, we compare the conflicting data on the involvement of suPAR in the pathogenesis of FSGS and shed light on interpretation by taking into account many points and the potential variables and confounders influencing serum suPAR levels.

Urokinase-type plasminogen activator in plasma from breast cancer patients

1988 ◽  
Vol 24 (9) ◽  
pp. 1553
Author(s):  
F. Bach ◽  
J. Grøndahl-Hansen ◽  
N. Agerlin ◽  
P. Munkholm-Larsen ◽  
L.S. Nielsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Plasminogen Activator ◽  
Breast Cancer Patients ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancers

2002 ◽  
Vol 30 (2) ◽  
pp. 207-210 ◽  
Author(s):  
M. J. Duffy
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Plasminogen Activator ◽  
Prospective Trial ◽  
Axillary Node ◽  
Prognostic Impact ◽  
Breast Cancer Patients ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Pai 1

Urokinase-type plasminogen activator (uPA) is a serine protease that is causally involved in cancer progression, especially invasion and metastasis. Multiple studies have shown that breast cancer patients whose primary cancer contains high levels of uPA have a significantly worse outcome than patients with low levels. As a prognostic marker for breast cancer the information supplied by uPA is both independent of traditionally used factors and significant in the important subgroup of axillary-node patients. Paradoxically, high levels of plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of uPA, also predict for aggressive disease. Recently, the prognostic impact of both uPA and PAI-1 in axillary node-negative breast cancer was confirmed using two different Level 1 Evidence studies, i.e. in both a randomized prospective trial and a pooled analysis. Therefore, uPA and PAI-1 appear to have fulfilled all the criteria for the routine assessment of prognosis in newly diagnosed breast cancer patients

scholarly journals A Pilot Study of Urokinase-Type Plasminogen Activator (uPA) Overexpression in the Brush Cytology of Patients with Malignant Pancreatic or Biliary Strictures

HPB Surgery ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-5 ◽  
Author(s):  
John F. Gibbs ◽  
Michael Schlieman ◽  
Paramvir Singh ◽  
Rakhee Saxena ◽  
Maisie Martinick ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Serum Levels ◽  
Pancreatic Tumors ◽  
Biliary Strictures ◽  
Endoscopic Retrograde ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Pancreaticobiliary Cancer ◽  
Larger Sample ◽  
Sensitive Marker

We have previously demonstrated that uPA is overexpressed in pancreatic tumors. In an attempt to diagnose these tumors earlier, we sought to determine whether uPA could be identified in endoscopic retrograde cholangiopancreatography obtained brushings in patients with malignant pancreatic and biliary strictures. Secondarily, uPA was measured in the serum of this patient population. uPA overexpression was identified in the cytologic tissue in 8 of 11 patients (72.7%). Serum analysis demonstrated a 2-fold higher concentration of uPA in the pancreaticobiliary cancer patients (1.27 versus 0.56 ng/mL; ). Also, uPA overexpression correlated with serum levels (). This study confirms that uPA can be detected in the ERCP cytologically obtained tissue and is frequently present in a higher concentration in the serum of pancreaticobiliary cancer patients. A larger sample size will be required to address its value as a sensitive marker for the diagnosis of pancreatic or biliary cancers.

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