Plasminogen Activator System and Breast Cancer: Potential Role in Therapy Decision Making and Precision Medicine

Gouri, Adel; Dekaken, Aoulia; Bairi, Khalid El; Aissaoui, Arifa; Laabed, Nihad; Chefrour, Mohamed; Ciccolini, Joseph; Milano, Gérard; Benharkat, Sadek

doi:10.4137/bmi.s33372

Cited by 26 publications

(28 citation statements)

References 69 publications

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“…EGFR is not only implicated in the promotion of tumour growth by promoting angiogenesis and revascularization, but EGFR signalling pathways are also related to up‐regulation of PLAU and PLAUR . Plasmin is also capable of activating several MMPs, including MMP3, which may lead to extracellular matrix degradation . Our network outcome model indicated that EGFR was significantly associated with lower mortality rates.…”

Section: Discussionmentioning

confidence: 99%

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic heart failure

Sama

Woolley

Nauta

et al. 2020

European J of Heart Fail

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Aims Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. Methods and results We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. Conclusions Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF.

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Section: Discussionmentioning

confidence: 99%

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic heart failure

Sama

Woolley

Nauta

et al. 2020

European J of Heart Fail

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“…Besides its roles in thrombosis and atherosclerosis, other roles related studies were relatively rare. However, studies indicated that PAI-1 is present in increased levels in various disease states (such as some forms of cancer), as well as in obesity and the metabolic syndrome [20-22]. In inflammatory conditions, PAI-1 appears to play a significant role in the progression to fibrosis, which is pathological formation of connective tissues.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Zhu¹,

Shen²,

Zhu³

et al. 2017

Cell Physiol Biochem

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Background: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression.

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“…The prognostic relevance of components of the plasminogen activator system has been intensively studied in various cancers (Duffy and Duggan 2004;Ferrier et al 2000;Baluka et al 2016). In breast cancer patients, high tissue levels of uPA and PAI-1 are associated with a poor prognosis, early disease relapse and predict treatment response and resistance (Foekens et al 2000;Borstnar et al 2002;Witte et al 1999b;Gouri et al 2016). High tissue levels of PAI-1 and uPA also led to a shorter DFS and OS in gastric, lung and ovarian cancer (Brungs et al 2017;Su et al 2015;Kuhn et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of VEGF and components of the plasminogen activator system in endometrial cancer

Abbink

Zusterzeel

Geurts-Moespot

et al. 2020

J Cancer Res Clin Oncol

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Objective The plasminogen activator system (PAS) and vascular endothelial growth factor (VEGF) are important in the carcinogenesis and play a key role in cancer invasion and mediating metastasis of carcinomas. The aim of the study was to evaluate the correlation of serum levels of VEGF and components of the PAS with clinicopathological risk factors and outcome in patients with endometrial cancer (EC). Methods Preoperative blood was collected from 173 patients treated for EC between 1999 and 2009. Serum concentrations of VEGF, urokinase plasminogen activator (uPA) tissue plasminogen activator (tPA), plasminogen activator inhibitor type-1 (PAI-1) and-2 (PAI-2) were assessed by enzyme-linked immunosorbent assays (ELISA). Results Serum levels of VEGF and components of the PAS were significantly associated with stage of the disease, tumor histology, tumor grade, myometrial invasion (MI), presence of lymphovascular space invasion (LVSI) and lymph node metastases (LNM). Preoperative serum levels of PAI-1 and-2 and tPA were higher in patients who experienced a recurrence than in patients who remained disease free (p < 0.01). PAI-1 and-2 and tPA were significantly independent prognostic factors for DFS with a HR of 3.85 (95% CI 1.84-8.07), 3.90 (95% CI 1.75-8.66) and 2.53 (95% CI 1.16-5.55), respectively. PAI-1 and tPA turned out to be independent prognostic factors for OS, with a HR of 2.09 (95% CI 1.08-4.05) and 2.16 (95% CI 1.06-4.44), respectively. Conclusion Serum levels of VEGF and components of the PAS at primary diagnosis were associated with well-known clinicopathological risk factors such as; FIGO stage, tumor histology, tumor grade, MI, LVSI and LNM. High concentrations of PAI-1 and-2 and tPA are independent factors for poor prognosis in patients with endometrial cancer.

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Plasminogen Activator System and Breast Cancer: Potential Role in Therapy Decision Making and Precision Medicine

Cited by 26 publications

References 69 publications

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic heart failure

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic heart failure

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Prognostic significance of VEGF and components of the plasminogen activator system in endometrial cancer

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