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      The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice

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          Abstract

          Essentials

          • Factor Xa (FXa)‐targeting direct oral anticoagulants (DOACs) reduce venous thromboembolism (VTE)

          • The effects of FXa‐targeting DOACs on cancer progression remain to be studied

          • In xenograft models, a FXa‐targeting DOAC did not inhibit breast cancer growth and metastasis

          • A thrombin‐targeting DOAC, dabigatran, also did not inhibit breast cancer growth and metastasis

          Abstract
          Background

          Factor Xa‐targeting DOACs were recently found to reduce recurrent VTE efficiently in cancer patients when compared to the standard treatment with low‐molecular‐weight heparins ( LMWHs). While the anticancer effects of LMWHs have been extensively studied in preclinical cancer models, the effects of FXa‐targeting DOACs on cancer progression remain to be studied.

          Objective

          We investigated whether the FXa‐targeting DOAC rivaroxaban and the thrombin‐targeting DOAC dabigatran etexilate ( DE) affected human breast cancer growth and metastasis in orthotopic xenograft models.

          Methods/results

          Mice that were put on a custom‐made chow diet supplemented with rivaroxaban (0.4 or 1.0 mg/g diet) or dabigatran etexilate ( DE) (10 mg/g diet) showed prolonged ex vivo coagulation times (prothrombin time [ PT] and activated partial thromboplastin time [ aPTT] assay, respectively). However, rivaroxaban and DE did not inhibit MDAMB‐231 tumor growth and metastasis formation in lungs or livers of 7‐week‐old fully immunodeficient NOD/ SCID/ ƴ C −/− ( NSG) mice. Comparable data were obtained for rivaroxaban‐treated mice when using NODSCID mice. Rivaroxaban and DE treatment also did not significantly inhibit tumor growth and metastasis formation when using another human triple negative breast cancer ( TNBC) cell line ( HCC1806) in NODSCID mice. The FXa and thrombin‐induced gene expression of the downstream target CXCL8 in both cell lines, but FXa and thrombin, did not significantly stimulate migration, proliferation, or stemness in vitro.

          Conclusion

          Although effectively inhibiting coagulation, the DOACs rivaroxaban and DE did not inhibit orthotopic growth and metastasis of human TNBC. It remains to be investigated whether DOACs exert antitumorigenic effects in other types of cancer.

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          Most cited references54

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          Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.

          Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer. Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months). During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group. In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding. Copyright 2003 Massachusetts Medical Society
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            Epidemiology of cancer-associated venous thrombosis.

            Cancer-associated venous thrombosis is a common condition, although the reported incidence varies widely between studies depending on patient population, start and duration of follow-up, and the method of detecting and reporting thrombotic events. Furthermore, as cancer is a heterogeneous disease, the risk of venous thrombosis depends on cancer types and stages, treatment measures, and patient-related factors. In general, cancer patients with venous thrombosis do not fare well and have an increased mortality compared with cancer patients without. This may be explained by the more aggressive type of malignancies associated with this condition. It is hypothesized that thromboprophylaxis in cancer patients might improve prognosis and quality of life by preventing thrombotic events. However, anticoagulant treatment leads to increased bleeding, particularly in this patient group, so in case of proven benefit of thromboprophylaxis, only patients with a high risk of venous thrombosis should be considered. This review describes the literature on incidence of and risk factors for cancer-associated venous thrombosis, with the aim to provide a basis for identification of high-risk patients and for further development and refinement of prediction models. Furthermore, knowledge on risk factors for cancer-related venous thrombosis may enhance the understanding of the pathophysiology of thrombosis in these patients.
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              Control of Metastasis by NK Cells.

              The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
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                Author and article information

                Contributors
                j.t.buijs@lumc.nl , https://twitter.com/jeroen_buijs
                Journal
                J Thromb Haemost
                J. Thromb. Haemost
                10.1111/(ISSN)1538-7836
                JTH
                Journal of Thrombosis and Haemostasis
                John Wiley and Sons Inc. (Hoboken )
                1538-7933
                1538-7836
                29 April 2019
                June 2019
                : 17
                : 6 ( doiID: 10.1111/jth.2019.17.issue-6 )
                : 951-963
                Affiliations
                [ 1 ] Einthoven Laboratory for Vascular and Regenerative Medicine Division of Thrombosis and Hemostasis Department of Internal Medicine Leiden University Medical Center Leiden The Netherlands
                [ 2 ] Division of Drug Discovery and Safety Leiden Academic Center for Drug Research Leiden University Leiden The Netherlands
                [ 3 ] Department of Urology Leiden University Medical Center Leiden The Netherlands
                Author notes
                [*] [* ] Correspondence

                Jeroen T. Buijs, Einthoven Laboratory for Vascular and Regenerative Medicine, Division of Thrombosis and Hemostasis, Dept. of Internal Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

                Email: j.t.buijs@ 123456lumc.nl

                Author information
                https://orcid.org/0000-0001-5816-9739
                https://orcid.org/0000-0003-4294-175X
                Article
                JTH14443
                10.1111/jth.14443
                6849835
                30929299
                9203664f-b8c5-4457-9e6e-3a33a6c886cf
                © 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 26 October 2018
                : 18 March 2019
                Page count
                Figures: 5, Tables: 0, Pages: 13, Words: 8221
                Funding
                Funded by: Dutch Cancer Society , open-funder-registry 10.13039/501100004622;
                Award ID: #2015‐7594
                Funded by: World Wide Cancer Research
                Award ID: #15‐1186
                Categories
                Original Article
                HAEMOSTASIS
                Original Articles
                Custom metadata
                2.0
                June 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:12.11.2019

                Hematology
                anticoagulants,breast neoplasms,dabigatran,factor x,rivaroxaban
                Hematology
                anticoagulants, breast neoplasms, dabigatran, factor x, rivaroxaban

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