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

Abstract

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.

The Plasminogen–Activator Plasmin System in Physiological and Pathophysiological Angiogenesis

“…PAI-2 is a potent uPA inhibitor that exists in two forms: a 47 kDa nonglycosylated intracellular form and a secreted 60 kDa glycosylated form, but exists mainly in the prior form. The expression of the PAI-2 SERPINB2 gene is induced by inflammatory mediators such as TNF-α and lipopolysaccharides or by viral and bacterial infections [ 119 , 120 , 121 ]. It is expressed constitutively by various cell types like keratinocytes and syncytial trophoblasts and is also expressed as a result of inflammation or injury by various cell types, including monocytes, macrophages, EC, and fibroblasts, highlighting its important role in mediating wound healing and inflammation [ 122 ].…”

“…PAI-2 levels are also elevated in trophoblasts emphasizing its vital role in embryogenesis; reduced plasma levels of PAI-2 in human embryos were associated with preeclampsia and intrauterine growth delay [ 121 ]. However, in vivo experiments on mice showed that mice deficient in PAI-2 exhibited normal development and survival [ 120 ]. Unlike PAI-1, elevated levels of PAI-2 in cancer are linked with reduced cancer progression and metastasis due to its inability to bind to vitronectin.…”

The Multifaceted Role of Plasminogen in Cancer

“…Decreased PAI-2 expression has been associated with increased tumor invasiveness and metastasis for several types of cancer. In 50% of PAI-2-deficient mice aged over 18 months, spontaneous malignancies of vascular origin were found [19]. Moreover, accelerated tumor growth was observed in PAI-2-deficient mice when injected with B16 melanoma or Lewis lung carcinoma cells.…”

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics

“…However, PAI-2 deficient mice had normal development, survival, fertility, and response to infections [143]. While no clear links with vascular disease have been documented, PAI-2 deficiency has shown an association with malignant tumour growth and metastasis by mechanisms that remain unclear [144].…”