Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis
Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastati...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.834472/full |
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| author | Marta Smeda Marta Stojak Kamil Przyborowski Magdalena Sternak Joanna Suraj-Prazmowska Kamil Kus Katarzyna Derszniak Katarzyna Derszniak Agnieszka Jasztal Agnieszka Kij Anna Kurpinska Anna Kieronska-Rudek Anna Kieronska-Rudek Kamila Wojnar-Lason Kamila Wojnar-Lason Elzbieta Buczek Tasnim Mohaissen Tasnim Mohaissen Stefan Chlopicki Stefan Chlopicki |
| author_facet | Marta Smeda Marta Stojak Kamil Przyborowski Magdalena Sternak Joanna Suraj-Prazmowska Kamil Kus Katarzyna Derszniak Katarzyna Derszniak Agnieszka Jasztal Agnieszka Kij Anna Kurpinska Anna Kieronska-Rudek Anna Kieronska-Rudek Kamila Wojnar-Lason Kamila Wojnar-Lason Elzbieta Buczek Tasnim Mohaissen Tasnim Mohaissen Stefan Chlopicki Stefan Chlopicki |
| author_sort | Marta Smeda |
| collection | DOAJ |
| description | Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity. |
| first_indexed | 2024-12-12T02:28:02Z |
| format | Article |
| id | doaj.art-ed5f7afb64734566845378aec5aeab9d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T02:28:02Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-ed5f7afb64734566845378aec5aeab9d2022-12-22T00:41:30ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-02-011310.3389/fphar.2022.834472834472Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated HaemostasisMarta Smeda0Marta Stojak1Kamil Przyborowski2Magdalena Sternak3Joanna Suraj-Prazmowska4Kamil Kus5Katarzyna Derszniak6Katarzyna Derszniak7Agnieszka Jasztal8Agnieszka Kij9Anna Kurpinska10Anna Kieronska-Rudek11Anna Kieronska-Rudek12Kamila Wojnar-Lason13Kamila Wojnar-Lason14Elzbieta Buczek15Tasnim Mohaissen16Tasnim Mohaissen17Stefan Chlopicki18Stefan Chlopicki19Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandFaculty of Chemistry, Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandDepartment of Pharmacology, Jagiellonian University Medical College, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandDepartment of Pharmacology, Jagiellonian University Medical College, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandFaculty of Pharmacy, Jagiellonian University Medical College, Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, PolandDepartment of Pharmacology, Jagiellonian University Medical College, Krakow, PolandActivation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity.https://www.frontiersin.org/articles/10.3389/fphar.2022.834472/fullbreast cancerpulmonary metastasisdabigatranthrombinplatelets |
| spellingShingle | Marta Smeda Marta Stojak Kamil Przyborowski Magdalena Sternak Joanna Suraj-Prazmowska Kamil Kus Katarzyna Derszniak Katarzyna Derszniak Agnieszka Jasztal Agnieszka Kij Anna Kurpinska Anna Kieronska-Rudek Anna Kieronska-Rudek Kamila Wojnar-Lason Kamila Wojnar-Lason Elzbieta Buczek Tasnim Mohaissen Tasnim Mohaissen Stefan Chlopicki Stefan Chlopicki Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis Frontiers in Pharmacology breast cancer pulmonary metastasis dabigatran thrombin platelets |
| title | Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis |
| title_full | Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis |
| title_fullStr | Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis |
| title_full_unstemmed | Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis |
| title_short | Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis |
| title_sort | direct thrombin inhibitor dabigatran compromises pulmonary endothelial integrity in a murine model of breast cancer metastasis to the lungs the role of platelets and inflammation associated haemostasis |
| topic | breast cancer pulmonary metastasis dabigatran thrombin platelets |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.834472/full |
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