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The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding

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Abstract

The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an abundant scientific literature that has pointed to a pro-angiogenic role, a growth and migration stimulatory function, and an anti-apoptotic activity, all directed toward promoting tumor growth, cancer cell survival, and metastasis. With uPA, PAI-1 is among the most reliable biomarkers and prognosticators in many cancer types. More recently, a novel pro-tumorigenic function of PAI-1 in cancer-related inflammation has been demonstrated. These multifaceted activities of PAI-1 in cancer progression are explained by the complex structure of PAI-1 and its multiple functions that go beyond its anti-fibrinolytic and anti-plasminogen activation activities. However, despite the multiple evidences supporting a pro-tumorigenic role of PAI-1 in cancer, and the development of several inhibitors, targeting PAI-1, has remained elusive. In this article, the various mechanisms responsible for the pro-tumorigenic functions of PAI-1 are reviewed with emphasis on its more recently described contribution to cancer inflammation. The challenges of targeting PAI-1 in cancer therapy are then discussed.

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Funding

This publication has been supported in part by grant CA129377 from the National Cancer Institute, National Institutes of Health to YDC. M.K was supported by a post-doctoral research career development award of the Saban Research Institute of Children’s Hospital Los Angeles.

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  1. Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA, 90033, USA

    Marta Helena Kubala & Yves Albert DeClerck

  2. The Saban Research Institute of Children’s Hospital, Los Angeles, CA, 90027, USA

    Marta Helena Kubala & Yves Albert DeClerck

  3. Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Yves Albert DeClerck

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Correspondence to Yves Albert DeClerck.

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Kubala, M.H., DeClerck, Y.A. The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding. Cancer Metastasis Rev 38, 483–492 (2019). https://doi.org/10.1007/s10555-019-09806-4

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