Abstract
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.
Highlights
The observation that platelet inhibition could hamper cancer metastasis dates back to the 1970s
3.2 Effects of Dabigatran Treatment on Pulmonary Fibrin Deposition, Plasma Thrombin Generation, and Activation of the Innate Immune System Alongside the Development of Metastasis in BALB/c Mice Injected With 4T1 Breast Cancer Cells
To verify whether the unfavourable effects of dabigatran on pulmonary metastasis could be related to inhibition of fibrin deposition or innate immune response, we quantitively analysed fibrin levels in the murine lungs (Figure 2A) in relation to thrombin generation in plasma (Figure 2B), interferon γ (IFNγ) concentration in lung homogenates (Figure 2C), and complement activation (Figure 2D)
Summary
The observation that platelet inhibition could hamper cancer metastasis dates back to the 1970s. The idea to hamper cancer metastasis via anticoagulant/antiplatelet therapy has re-emerged due to the development of novel potent oral anticoagulants (NOACs), which affect pathways of platelet activation and thrombus formation that are independent of cyclooxygenase 1-dependent thromboxane A2 production, a pathway inhibited by aspirin. NOACs were shown to reduce cancer metastasis (DeFeo et al, 2010; Alexander et al, 2015) several studies provide evidence for the lack of antimetastatic effects of these compounds (Alexander et al, 2015; Buijs et al, 2019), and some even suggest detrimental effects (Niers et al, 2009; Shi et al, 2017). Dabigatran effectively inhibited metastatic spread in some studies (DeFeo et al, 2010), in another studies it was ineffective (Alexander et al, 2015; Buijs et al, 2019), or it increased metastatic seeding (Shi et al, 2017)
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