Deficiency of plasminogen activator inhibitor‐2 results in accelerated tumor growth

• Published in: Journal of thrombosis and haemostasis Vol. 18; no. 11; pp. 2968 - 2975
• Main Authors: Westrick, Randal J., Røjkjær, Lisa Payne, Yang, Angela Y., Roh, Michael H., Siebert, Amy E., Ginsburg, David
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01-11-2020
• Subjects: Animals; Bone marrow transplantation; cancer; Extracellular matrix; fibrinolysis; Invasiveness; Lung carcinoma; Malignancy; Melanoma; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; PAI‐2; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2 - genetics; Plasminogen activator inhibitors; Proteinase inhibitors; Proteolysis; Serine; serine protease inhibitor; Serine proteinase; Serpins - genetics; tumor; Tumor cells; Tumorigenesis; U-Plasminogen activator; Urokinase-Type Plasminogen Activator; fibrinolysis; PAI-2; cancer; serine protease inhibitor; tumor
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.15054

Background
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.
Objectives
We investigated the role of PAI‐2 deficiency on tumor growth and metastasis.
Methods
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.
Results and Conclusions
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.