Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis

Sier, Cornelis F.M.; Vloedgraven, H. J. M.; Ganesh, S.; Griffioen, G.; Quax, Paul H.A.; Verheijen, J.H.; Dooijewaard, G.; Welvaart, K; Velde, Cornelis J.H. van de; Lamers, C. B. H. W.; Verspaget, Hein W.

doi:10.1016/0016-5085(94)90549-5

Cited by 62 publications

(36 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By inhibiting apoptosis in tumour cells, PAI-1 can potentially increase the aggressiveness of the tumour, supporting the previous observations that PAI-1 is a poor prognostic indicator (Foekens et al, 1994;Kuhn et al, 1994;Pedersen et al, 1994;Sier et al, 1994;Hofmann et al, 1996;Sugiura et al, 1999). On the other hand, when PAI-1 expression is increased within tumour cells as a result of transfection, the tumour invasiveness and metastatic potential is decreased (Cajot et al, 1990;Alizadeh et al, 1995;Soff et al, 1995).…”

Section: Figuresupporting

confidence: 83%

True

et al. 2000

View full text Add to dashboard Cite

Plasminogen activator inhibitor 1 (PAI-1) has been found to be a bad prognostic factor in a number of tumours but the reason has not been fully explained. The human prostate cancer cell line PC-3 and the human promyelocytic leukaemia cell line HL-60 were used in this study to determine the effect of PAI-1 on spontaneous and induced apoptosis in culture. Apoptosis was induced with camptothecin or etoposide. Addition of a stable variant of PAI-1 or wild-type PAI-1 to these cells resulted in a significant inhibition of apoptosis. In contrast, both the latent form of PAI-1 and the stable variant of PAI-1 inactivated by a specific neutralizing monoclonal antibody, or the stable variant of PAI-1 in a complex with recombinant urokinase did not inhibit apoptosis. This indicated that the inhibitory activity of PAI-1 was required for its anti-apoptotic effect but the urokinase-type plasminogen activator receptor was not involved. These findings provide an explanation for the bad prognostic correlation of high PAI-1 levels in tumours. The anti-apoptotic effect was also found in non-tumoural cells including human umbilical vein endothelial cells and the benign human breast epithelial cell line MCF-10A, suggesting that this is a novel physiologic function of PAI-1. © 2000 Cancer Research Campaign

show abstract

Section: Figuresupporting

confidence: 83%

True

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Assays for urokinase, urokinase receptor, plasminogen activator inhibitors, matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases Total antigen levels of urokinase plasminogen activator (uPA), plasminogen activator inhibitors (PAI-1 and -2), urokinase plasminogen activator receptor, matrix metalloproteinases (MMP-2, -7, -8, -9) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and -2) were determined using previously described ELISAs Sier et al, 1994;Hanemaaijer et al, 1998;Kubben et al, 2006). The bioactivity assays for uPA, MMP-2 and MMP-9 were performed as described before (Hanemaaijer et al, 1998;Sier et al, 2000;Kubben et al, 2006).…”

Section: Elisa For Total and Active Tgf-b1mentioning

confidence: 99%

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

et al. 2007

View full text Add to dashboard Cite

Transforming growth factor-b1 (TGF-b1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-b1 activation and localisation of TGF-b1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-b1 staining by immunohistochemistry. Active TGF-b1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-b1. Active TGF-b1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-b1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGFb1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGFb1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-b1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-b1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-b1 activity levels in gastric cancer.

show abstract

“…PAI1 may also be directly involved in cancer progression. Both tumor cells and capillary endothelial cells express higher levels of PAI1 than other cell types [7][8][9] . Surprisingly, this inhibitor is necessary for optimal invasion of cultured lung cancer cells 10 , and an increasing number of clinical studies have demonstrated that high PAI1 levels indicate a poor prognosis for the survival of patients suffering from a variety of cancers [11][12][13] .…”

mentioning

confidence: 99%

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Bajou

Noël

Gerard

et al. 1998

Nat Med

623

474

View full text Add to dashboard Cite

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angio-genesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.Tumor cell invasion and metastatic processes require the coordinated and temporal regulation of a series of adhesive, proteolytic and migratory events 1 . The plasminogen activator (PA)-plasmin proteolytic system has been implicated in these processes. Urokinase-type (uPA) and tissue-type (tPA) plasminogen activators are serine proteases that catalyze the conversion of inactive plasminogen into plasmin, a broadly acting enzyme able to degrade a variety of extracellular matrix proteins and to activate metalloproteinases and growth factors 2,3 . Plasminogen and uPA bind to their specific receptors directing plasmin activity to the migrating tumor cell surface. The activities of PA are directly controlled by specific inhibitors, the PA inhibitors 1 and 2 (PAI1 and PAI2) (ref. 4).Many studies have focused on the role of uPA in cellular invasion and metastasis. Much of the data supporting the role of uPA in these events derives from in vitro and in vivo experiments demonstrating a correlation between uPA expression and cell invasion and metastasis as well as reduction of metastatic potential by using natural or synthetic serine protease inhibitors, neutralizing antibodies to uPA or antisense oligonucleotides 5,6 . PAI1 may also be directly involved in cancer progression. Both tumor cells and capillary endothelial cells express higher levels of PAI1 than other cell types [7][8][9] . Surprisingly, this inhibitor is necessary for optimal invasion of cultured lung cancer cells 10 , and an increasing number of clinical studies have demonstrated that high PAI1 levels indicate a poor prognosis for the survival of patients suffering from a variety of cancers [11][12][13] . However, as PAI1 is an acute-phase reactant 14 , it remains undetermined whether the increased PAI1 levels causally contribute to, or rather are the consequence of, the malignancy.Various observations indicate that the PA system may provide both surface-associated protease activity and an adhesion mechanism for cells through interaction with vitronectin. Deng et al. suggested that the balance between cell adhesion and cell detachment is governed by PAI1 (ref. 15). The PAI1-mediated release of cells attached to vitronectin seems to occur independently of the abili...

show abstract

Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis

Cited by 62 publications

References 37 publications

True

True

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Contact Info

Product

Resources

About