Venous thromboembolism (VTE) is increased in cancer patients and is commonly referred to as cancer- associated thrombosis (CAT). Rates of VTE vary among different cancer types with pancreatic cancer having one of the highest rates of CAT (12-42%). This suggests that there are cancer type-specific mechanisms of VTE. We and others have used mouse models to investigate mechanisms of CAT in different types of cancer. Our previous studies have shown that tumor-derived tissue factor (TF) increases thrombus size in mice bearing human pancreatic tumors in a new model of CAT. We will build on this observation by determining the role of the intrinsic coagulation pathway, neutrophils/neutrophil extracellular traps (NETs) and tumor-derived and host-derived plasminogen activator inhibitor type-1 (PAI-1) in venous thrombosis in tumor-bearing mice. We have found that mice bearing human and murine pancreatic tumors have increased levels of circulating FIXa-antithrombin (AT) complexes (indicating activation of the intrinsic coagulation cascade), neutrophils, plasma citrullinated histone H3 (H3Cit) (indicating increased NET formation), and increased levels of PAI-1 (indicating a hypofibrinolytic state). In this proposal. we will use xenograft and allograft mouse models as well as multiple human and murine pancreatic cancer cell lines and patients derived xenografts. We will use genetic and pharmacologic approaches to comprehensively determine the roles of the intrinsic coagulation pathway, neutrophils, NETs and PAI-1 in pancreatic CAT. Targeting the intrinsic pathway, neutrophils/NETs and PAI-1 may reduce VTE in pancreatic cancer patients with less risk of bleeding.

Public Health Relevance

This project will determine the pathways that contribute to venous thrombosis in pancreatic cancer patients. We will use genetic and pharmacologic approaches to determine the role of the different pathways in mouse models of pancreatic cancer. Targeting these pathways may reduce venous thrombosis in pancreatic cancer patients with less risk of bleeding.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL147149-02
Application #
9928103
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kindzelski, Andrei L
Project Start
2019-05-15
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599