Role of neutrophils and neutrophil extracellular traps in mice bearing human pancreatic tumors

Background : Pancreatic cancer is associated with high incidence of venous thromboembolism (VTE). Neutrophils have been shown to contribute to thrombosis in part by releasing neutrophil extracellular traps (NETs). A recent clinical study showed that increased plasma levels of the NET biomarker, citrullinated histone H3 (H3Cit), are associated with VTE in pancreatic and lung cancer but not in other types of cancer, including breast cancer.

Aims : To determine the contribution of neutrophils and NETs to venous thrombosis in mice bearing human pancreatic tumors.

Methods : Nude mice bearing human pancreatic BxPc- 3 tumors were used. Thrombosis was induced by inferior vena cava stasis.

Results : We found that tumor- bearing mice had increased circulating neutrophil counts and levels of granulocyte- colony stimulating factor, neutrophil elastase, H3Cit and cell- free DNA compared with controls. In addition, thrombi from tumor- bearing mice contained increased levels of the neutrophil marker Ly6G, as well as higher levels of H3Cit and extracellular DNA. Thrombi from tumor- bearing mice also had thinner fibrin fibers consistent with increased thrombin generation. Importantly, neutrophil depletion and administration of DNase I reduced thrombus size in tumor- bearing but not in control mice.

Conclusions : Our data indicate that neutrophils and NETs contribute to venous thrombosis in a mouse model of pancreatic cancer. Targeting this pathway may prevent VTE in pancreatic cancer patients without increasing bleeding.