Abstract Number: OC 41.3
Meeting: ISTH 2021 Congress
Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid tumor malignancy with a 5-year survival rate of 9%. PDAC is associated with robust coagulation system activity, including high circulating levels of thrombin-antithrombin complexes and fibrin-degradation products. Local coagulation and fibrinolytic activity have also been documented in the PDAC tumor microenvironment, but a functional connection to PDAC progression has not been established.
Aims: To determine possible mechanistic roles of fibrinogen and plasminogen in PDAC tumor growth and metastasis.
Methods: Human PDAC patient and KPC (KRasG12D, TRP53R172H) PDAC mouse model tumor samples were examined for fibrin expression by immunohistochemical staining. Orthotopic allograft primary tumor growth and experimental metastasis assays were performed with mouse KPC PDAC tumor cells in mice carrying null or functional mutations in fibrinogen and plasminogen. Human low passage PDAC tumor growth was similarly analyzed following pharmacological fibrinogen/plasminogen reduction in NSG mice.
Results: Substantial fibrin deposition was observed within and around primary tumor lesions of both PDAC patients and mouse PDAC models. However, mice with fibrinogen-deficiency (Fib-/-) or fibrinogen mutations disrupting fibrin polymer formation (FibAEK) or leukocyte engagement (Fibg390-396A) did not affect tumor growth or metastasis. Interestingly, both genetically-imposed plasminogen deficiency (Plg-/-) and pharmacological plasminogen reduction with antisense oligonucleotides significantly reduced primary tumor growth and metastasis of mouse KPC and human low passage PDAC tumor cells, respectively. Reduced tumor growth was linked to reduced tumor cell proliferation.
Conclusions: Plasminogen, but not fibrinogen, promotes PDAC tumor growth and metastasis, a functional connection between the fibrinolytic system and multiple stages of PDAC progression.
To cite this abstract in AMA style:Yang Y, Abrahams S, Davey K, Revenko A, Fishel M, Wolberg A, Flick M. Plasminogen, but Not Fibrinogen, Promotes Pancreatic Ductal Adenocarcinoma Tumor Growth and Metastasis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/plasminogen-but-not-fibrinogen-promotes-pancreatic-ductal-adenocarcinoma-tumor-growth-and-metastasis/. Accessed December 7, 2021.
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