Deficiency of plasminogen activator inhibitor-2 results in accelerated tumor growth.

Randal J Westrick, Lisa Payne Røjkjaer, Angela Y Yang, Michael H Roh, Amy E Siebert, David Ginsburg

Journal of thrombosis and haemostasis : JTH 2020 Nov

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Upregulation of the plasminogen activation system, including urokinase plasminogen activator (uPA), has been observed in many malignancies, suggesting that co-opting the PA system is a common method by which tumor cells accomplish extracellular matrix proteolysis. PAI-2, a serine protease inhibitor, produced from the SERPINB2 gene, inhibits circulating and extracellular matrix-tethered uPA. Decreased SERPINB2 expression has been associated with increased tumor invasiveness and metastasis for several types of cancer. PAI-2 deficiency has not been reported in humans and PAI-2-deficient (SerpinB2-/- ) mice exhibit no apparent abnormalities. We investigated the role of PAI-2 deficiency on tumor growth and metastasis. To explore the long-term impact of PAI-2 deficiency, a cohort of SerpinB2-/- mice were aged to >18 months, with spontaneous malignancies observed in 4/9 animals, all of apparently vascular origin. To further investigate the role of PAI-2 deficiency in malignancy, SerpinB2-/- and wild-type control mice were injected with either B16 melanoma or Lewis lung carcinoma tumor cells, with markedly accelerated tumor growth observed in SerpinB2-/- mice for both cell lines. To determine the relative contributions of PAI-2 from hematopoietic or nonhematopoietically derived sources, bone marrow transplants between wild-type C57BL/6J and SerpinB2-/- mice were performed. Our results suggest that PAI-2 deficiency increases susceptibility to spontaneous tumorigenesis in the mouse, and demonstrate that SerpinB2 expression derived from a nonhematopoietic compartment is a key host factor in the regulation of tumor growth in both the B16 melanoma and Lewis lung carcinoma models. © 2020 International Society on Thrombosis and Haemostasis.

Citation

Randal J Westrick, Lisa Payne Røjkjaer, Angela Y Yang, Michael H Roh, Amy E Siebert, David Ginsburg. Deficiency of plasminogen activator inhibitor-2 results in accelerated tumor growth. Journal of thrombosis and haemostasis : JTH. 2020 Nov;18(11):2968-2975