Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing

Placencio, Veronica R.; DeClerck, Yves A.

doi:10.1158/0008-5472.can-15-0876

Cited by 156 publications

(144 citation statements)

References 54 publications

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“…This highlights the importance of the stromal production of PAI-1 within the tumour microenvironment [9], as only methods that took into account both stromal and tumour PAI-1 showed statistically significant prognostic outcomes. It has been postulated that in contrast to uPAR, fibroblasts and endothelial cells provide the major source of PAI-1 within the tumour tissue [45].…”

Section: Discussionmentioning

confidence: 96%

The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis

et al. 2017

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BackgroundThe urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. Although there is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain.ResultsWe identified 22 studies encompassing 1966 patients which fulfilled the inclusion criteria. uPA, uPAR, or PAI-1 expression is significantly associated with high risk clinicopathological features. High uPA expression is associated with a shorter RFS (HR 1.90 95% 1.16–3.11, p = 0.01) and OS (HR 2.21 95% CI 1.74–2.80, p < 0.0001). High uPAR expression is associated with poorer OS (HR 2.21 95%CI 1.82–2.69, p < 0.0001). High PAI-1 expression is associated with shorter RFS (HR 1.96 96% CI 1.07–3.58, p = 0.03) and OS (HR 1.84 95%CI 1.28–2.64, p < 0.0001). There was no significant association between PAI-2 expression and OS (HR 0.97 95%CI 0.48–1.94, p < 0.92) although data was limited.Materials and MethodsWe undertook a systematic review evaluating expression of uPA, urokinase plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1/SerpinE1) and plasminogen activator inhibitor-2 (PAI-2/SerpinB2) on primary oesophageal, gastro-oesophageal junction, and gastric adenocarcinomas. We performed a meta-analysis of clinicopathological associations, overall survival (OS) and recurrence free survival (RFS).ConclusionsWe conclude that the uPA system is a clinically relevant biomarker in primary gastroesophageal cancer, with higher expression of uPA, uPAR and PAI-1 associated with higher risk disease and poorer prognosis. This also highlights the potential utility of the uPA system as a therapeutic target for improved treatment strategies.

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Section: Discussionmentioning

confidence: 96%

The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis

et al. 2017

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“…PAI-1 is a protein encoded by the gene SERPINE1 and belongs to the class of serine protease inhibitors. It is the principal component of the plasminogen system, which is upregulated in inflammation and cancer (14). EMT facilitates cell migration and is central for tumor cell dissemination (15).…”

Section: Introductionmentioning

confidence: 99%

Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasisassociated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy.

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“…The first evidence illuminating the link of PAI-1 to more aggressive cancers came from the observation that PAI-1 possesses a proangiogenic property via its anti-protease and vitronectin-binding functions facilitating the detachment of endothelial cells from vitronectin and their movement to fibronectin rich tissues [120,121]. Nonetheless, this angiogenesis activity is dose-dependent with a stimulatory activity at physiologic levels [120,122] and a suppressive activity at pharmacologic levels [123].…”

Section: Plasminogen Activator Inhibitor-1 (Pai-1)mentioning

confidence: 99%

Diabetes-associated dysregulated cytokines and cancer

Wu¹,

Liu²,

Dong³

et al. 2016

Integr Cancer Sci Therap

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Epidemiological data demonstrate that patients with diabetes have an augmented risk of developing various types of cancers, accompanied by higher mortality. A number of mechanisms for this connection have been hypothesized, such as insulin resistance, hyperinsulinemia, hyperglycemia, and increased inflammatory processes. Apart from these potential mechanisms, several diabetes-associated dysregulated cytokines might be implicated in the link between diabetes and cancer. In fact, some inflammatory cytokines, e.g. TNF-α, IL-6 and leptin, have been revealed to play important roles in both initiation and progression of tumor. Here, we depict the role of these cytokines in key events of carcinogenesis and cancer development, including their capability to induce oxidative stress, inflammation, their participation in epithelial mesenchymal transition (EMT), angiogenesis, and metastasis. Finally, we will also highlight the existing knowledge in terms of the involvement of these cytokines in different cancer types and comment on potential significances for future clinical applications.

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Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing

Cited by 156 publications

References 54 publications

The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis

The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis

Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression

Diabetes-associated dysregulated cytokines and cancer

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