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      Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications

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          Abstract

          The plasminogen activator (PA) system is an extracellular proteolytic enzyme system associated with various physiological and pathophysiological processes. A large body of evidence support that among the various components of the PA system, urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) play a major role in tumor progression and metastasis. The binding of uPA with uPAR is instrumental for the activation of plasminogen to plasmin, which in turn initiates a series of proteolytic cascade to degrade the components of the extracellular matrix, and thereby, cause tumor cell migration from the primary site of origin to a distant secondary organ. The components of the PA system show altered expression patterns in several common malignancies, which have identified them as ideal diagnostic, prognostic, and therapeutic targets to reduce cancer-associated morbidity and mortality. This review summarizes the various components of the PA system and focuses on the role of uPA–uPAR in different biological processes especially in the context of malignancy. We also discuss the current state of knowledge of uPA–uPAR-targeted diagnostic and therapeutic strategies for various malignancies.

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          Breast cancer metastasis: markers and models.

          Breast cancer starts as a local disease, but it can metastasize to the lymph nodes and distant organs. At primary diagnosis, prognostic markers are used to assess whether the transition to systemic disease is likely to have occurred. The prevailing model of metastasis reflects this view--it suggests that metastatic capacity is a late, acquired event in tumorigenesis. Others have proposed the idea that breast cancer is intrinsically a systemic disease. New molecular technologies, such as DNA microarrays, support the idea that metastatic capacity might be an inherent feature of breast tumours. These data have important implications for prognosis prediction and our understanding of metastasis.
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            Metastasis: a question of life or death.

            The metastatic process is highly inefficient--very few of the many cells that migrate from the primary tumour successfully colonize distant sites. One proposed mechanism to explain this inefficiency is provided by the cancer stem cell model, which hypothesizes that micrometastases can only be established by tumour stem cells, which are few in number. However, recent in vitro and in vivo observations indicate that apoptosis is an important process regulating metastasis. Here we stress that the inhibition of cell death, apart from its extensively described function in primary tumour development, is a crucial characteristic of metastatic cancer cells.
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              Models, mechanisms and clinical evidence for cancer dormancy.

              Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/470522
                URI : http://frontiersin.org/people/u/491017
                URI : http://frontiersin.org/people/u/166445
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                12 February 2018
                2018
                : 8
                Affiliations
                [1] 1Department of Medicine, McGill University Health Centre , Montreal, QC, Canada
                [2] 2Department of Oncology, McGill University Health Centre , Montreal, QC, Canada
                Author notes

                Edited by: Francois X. Claret, University of Texas MD Anderson Cancer Center, United States

                Reviewed by: Kara Lea Vine, University of Wollongong, Australia; Harikumar K. B., Rajiv Gandhi Centre for Biotechnology, India

                *Correspondence: Shafaat A. Rabbani, shafaat.rabbani@ 123456mcgill.ca

                Specialty section: This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00024
                5816037
                67349d7b-aa52-47f1-acd9-28a3d78411d3
                Copyright © 2018 Mahmood, Mihalcioiu and Rabbani.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 264, Pages: 21, Words: 19085
                Funding
                Funded by: Canadian Institutes of Health Research 10.13039/501100000024
                Award ID: MOP 130410
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                upa,urokinase-type plasminogen activator receptor,plasminogen activator system,plasminogen activator inhibitor-1,pai-2,atn-658,metastasis,cancer imaging

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