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

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.

Clot stabilization for the prevention of bleeding.

Coagulation is a finely tuned sequence of reactions beginning with the interaction between tissue factor (TF) and its substrate, factor VII (FVII), and resulting in the formation of a fibrin clot localized to the site of vascular endothelial disruption. While important for fibrin clot formation, thrombin also plays a role in stabilizing the clot against premature fibrinolysis by activating thrombin activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII), the terminal enzyme in the coagulation cascade. Despite use of antifibrinolytic agents in various types of surgery to inhibit clot lysis. thereby limiting blood loss and patient exposure to allogeneic blood products, numerous patients still require transfusions for nonsurgical bleeding. This article describes new concepts of localized hemostasis, a potential role for clot stabilization, and inhibition of fibrinolysis for control of bleeding.