Abstract 2002: Targeting the urokinase plasminogen activation pathway reduces PDAC cancer progression

Background: Multiple sclerosis (MS) is an autoimmune disorder where a breakdown in the integrity of the blood-brain barrier is thought to allow lymphocytes to enter the central nervous system. Objectives: The purpose of this study was to examine gene expression profiles between MS patients and healthy controls to identify genes intimately involved in the pathobiology of MS. Methods: Whole-genome gene expression analysis was performed using peripheral blood mononuclear cells from 39 healthy controls and 37 MS patients, 24 MS patients receiving no disease modifying therapy and 13 MS patients receiving interferon-beta (IFN-beta). Pathway analysis was performed to identify pathways dysregulated in MS. Results: Gene expression profiling of MS identified a signature of predominately immune associated genes. The plasminogen activation pathway contained an over-representation of significantly differentially expressed genes, including matrix metallopeptidase 9 (MMP9). Treatment with IFN-beta ameliorated the over-expression of MMP9, however the expression of two genes, plasminogen activator urokinase (PLAU) and serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), forming part of the plasminogen activation pathway were not affected by IFN-beta therapy. Conclusions: High expression levels of MMP9 have been associated with MS and the breakdown of the blood-brain barrier, while IFN-beta therapy decreases MMP9 expression. We confirm altered MMP9 expression in MS, and identify dysregulation within the plasminogen activation cascade, a pathway involved in the activation of MMP9.

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Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

Cancers ◽

10.3390/cancers13081838 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1838

Author(s):

Alamelu G. Bharadwaj ◽

Ryan W. Holloway ◽

Victoria Miller ◽

David Waisman

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Cancer Progression ◽

Cancer Diagnosis ◽

Stromal Cells ◽

Plasminogen Activation ◽

Malignant Cells ◽

Plasminogen Activation System ◽

Activation System ◽

Pai 1

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

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