ABSTRACT
Pancreatic cancer patients have a high risk of venous thromboembolism (VTE). Plasminogen activator inhibitor 1 (PAI-1) inhibits plasminogen activators and increases the risk of thrombosis. PAI-1 is expressed by pancreatic tumors and human pancreatic cell lines. However, to date, there are no studies analyzing the association of active PAI-1 and VTE in pancreatic cancer patients. We investigated the association of active PAI-1 in plasma and VTE in pancreatic cancer patients. In addition, we determined if the presence of human pancreatic tumors expressing PAI-1 impairs venous thrombus resolution in mice. Plasma levels of active PAI-1 in patients with pancreatic cancer and mice bearing human tumors were determined by enzyme-linked immunosorbent assay. We measured PAI-1 expression in 5 different human pancreatic cancer cell lines and found that PANC-1 cells expressed the highest level. PANC-1 tumors were grown in nude mice. Venous thrombosis was induced by complete ligation of the inferior vena cava (IVC). Levels of active PAI-1 were independently associated with increased risk of VTE in patients with pancreatic cancer (subdistribution hazard ratio per doubling of levels: 1.39 [95% confidence interval, 1.09-1.78], P = .007). Mice bearing PANC-1 tumors had increased levels of both active human and active mouse PAI-1 and decreased levels of plasmin activity. Importantly, mice bearing PANC-1 tumors exhibited impaired venous thrombus resolution 8 days after IVC stasis compared with nontumor controls. Our results suggest that PAI-1 contributes to VTE in pancreatic cancer.
Subject(s)
Pancreatic Neoplasms , Venous Thrombosis , Animals , Disease Models, Animal , Humans , Mice , Mice, Nude , Pancreatic Neoplasms/complications , Plasminogen Activator Inhibitor 1/genetics , Venous Thrombosis/etiologyABSTRACT
BACKGROUND: Some clinical studies have shown that low-molecular-weight heparins (LMWHs) prolong the survival of cancer patients. In addition, various anticoagulants have been shown to reduce growth of tumors in mice. However, there are no studies on the effect of the factor Xa inhibitor rivaroxaban on growth of human pancreatic tumors in nude mice. OBJECTIVES: To test the hypothesis that the factor Xa inhibitor rivaroxaban reduces the growth of tissue factor (TF)-positive pancreatic tumors but not TF-negative pancreatic tumors in mice. METHODS: The TF-positive human pancreatic cancer cell line BxPc-3 and the TF-negative human pancreatic cancer cell line MIA PaCa-2 were injected subcutaneously into nude mice and tumors grown to a mean volume of ~100 mm3 . Mice were then divided into two groups. One group was fed chow containing rivaroxaban (0.5 g/kg chow) whereas the other group was fed chow without rivaroxaban. RESULTS: Rivaroxaban significantly prolonged prothrombin time in tumor-bearing mice. Rivaroxaban did not affect cell proliferation or growth of either BxPc-3 or MIA PaCa-2 tumors grown subcutaneously in nude mice. CONCLUSION: Our results indicate that inhibition of factor Xa with rivaroxaban does not affect the growth of two human pancreatic tumors in nude mice.
