Long‐term thrombin inhibition promotes cancer cell extravasation in a mouse model of experimental metastasis

Niers, Tatjana M.H.; Brüggemann, Lois W.; Sluis, Geerte L. van; Liu, R. D.; Versteeg, Henri H.; Büller, Harry R.; Noorden, C. J. F. van; Reitsma, Pieter H.; Spek, C. Arnold; Richel, Dick J.

doi:10.1111/j.1538-7836.2009.03529.x

Cited by 15 publications

(24 citation statements)

References 13 publications

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“…The 9 selected publications included a total of 19 in vivo experiments (Table 1). Experiments were conducted in mice (n = 18) or rats (n = 1) of both male and female sex; and included carcinogenicity studies [28], spontaneous breast cancer [24], subcutaneous (fibrosarcoma [24], colorectal [24] and pancreatic cancer [25]), orthotopic (pancreatic [28,32] and breast cancer [29,31,23]) and experimental metastasis models (melanoma [27] and ovarian cancer [30]). The number of animals per treatment group ranged from 4 to 50.…”

Section: Description Of the Included Experimentsmentioning

confidence: 99%

“…The other studies declared no potential conflict of interest. Compliance with animal welfare regulations or an approved animal license was reported in 8 (8/9, 89%) studies, except in the study that was published as a letter to the editor [27].…”

Section: Description Of the Included Experimentsmentioning

confidence: 99%

“…The effect of ximelagatran treatment on lung metastasis formation was described by Niers et al in a syngeneic experimental metastasis model in which 1.5-3 × 10 5 B16F10 melanoma cells were inoculated into the tail vein of SCID mice (n = 11-13) [27]. Mice that were administered ximelagatran in the diet (250 μmol/kg/day, in food pellets) from 7 days before until 24 h before cancer cell inoculation demonstrated a two-fold induction in the number of lung metastases [27].…”

Section: Description Of the Included Studiesmentioning

confidence: 99%

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A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models

Najidh

Versteeg

Buijs

2020

Thrombosis Research

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Background: Direct oral anticoagulants (DOACs) are now the first choice thromboprophylaxis in cancer patients who do not have a high risk of bleeding. In addition to the anticoagulant effects, potential anti-tumor effects of DOACs have also been studied in animal cancer models. In this study, we summarize the effects of DOACs on cancer growth and metastasis in animal models through a systematic review with a qualitative analysis. Methods: PubMed, EMBASE and Web of Science were systematically searched for original studies that describe animal models of cancer in which one of the experimental groups received DOAC monotherapy, and which reported quantitatively on primary tumor or metastases. Results: Nine studies-reporting a total of 19 animal experiments-met the inclusion criteria. These 19 experiments included spontaneous cancer (n = 2), carcinogenicity (n = 2), xenograft (n = 7) and syngeneic (n = 8) models, encompassing orthotopic (n = 7), subcutaneous (n = 5), intraperitoneal (n = 1) and intravenous (n = 2) injection of cancer cells and included treatments with the DOACs ximelagatran (n = 4), dabigatran etexilate (n = 6) and/or rivaroxaban (n = 11). DOAC treatment decreased tumor growth at implanted and metastatic site in 18.8% (3/16) and 20.0% (3/15) of the experiments, respectively. Conversely, DOACs increased tumor growth at implanted and metastatic site in 6.3% (1/16) and 20.0% (3/15) of the experiments, respectively. Conclusion: DOAC monotherapy resulted in neoplastic changes in a rat carcinogenicity study, showed a lack of effect in mouse xenograft models, while the effect on cancer growth and metastasis in mouse syngeneic models depended on the timing of DOAC treatment and type of cancer model used.

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Section: Description Of the Included Experimentsmentioning

confidence: 99%

Section: Description Of the Included Experimentsmentioning

confidence: 99%

Section: Description Of the Included Studiesmentioning

confidence: 99%

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A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models

Najidh

Versteeg

Buijs

2020

Thrombosis Research

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“…However, the dose of hirudin used led to an excessive anticoagulation affect that is not compatible with the clinical use. Conversely, a continuous treatment with an oral thrombin inhibitor led to an accelerated pulmonary metastasis [39].…”

Section: Anticoagulant Activity and Metastasismentioning

confidence: 99%

Antimetastatic activities of heparins and modified heparins. Experimental evidence

Borsig

2010

Thrombosis Research

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Heparin is commonly used for prevention or treatment of cancer-associated thromboembolism. Recent clinical evidence indicates that heparin, and low-molecular weight heparin improves survival of cancer patients. Experimental evidence from various animal models consistently supports the ability of heparin to attenuate metastasis. Heparin, apart from its anticoagulant activity contains a variety of biological activities possibly affecting cancer progression, including: inhibition of heparanase, blocking of P-and L-selectin mediated cell adhesion, and inhibition of angiogenesis. The delineation of antimetastatic activity of heparin is in the focus of several ongoing investigations. This review summarizes the current experimental evidence on the biology of heparin as a potential treatment cancer progression. 3

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“…Cells were cultured in Dulbecco Modified Eagle Medium (DMEM; Lonza, Verviers, Belgium) supplemented with 10% fetal calf serum (Sigma-Aldrich), 1% penicillin-streptomycin solution and 1% L-glutamine at 37°C as described before [29], [30]. Single cell suspensions were prepared from 2 mM EDTA-treated monolayer's which were washed and diluted in phosphate-buffered saline (PBS) prior to counting and inoculation.…”

Section: Methodsmentioning

confidence: 99%

A Low Molecular Weight Heparin Inhibits Experimental Metastasis in Mice Independently of the Endothelial Glycocalyx

et al. 2010

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BackgroundSome low molecular weight heparins (LMWHs) prolong survival of cancer patients and inhibit experimental metastasis. The underlying mechanisms are still not clear but it has been suggested that LMWHs (at least in part) limit metastasis by preventing cancer cell-induced destruction of the endothelial glycocalyx.Methodology/Principal FindingsTo prove or refute this hypothesis, we determined the net effects of the endothelial glycocalyx in cancer cell extravasation and we assessed the anti-metastatic effect of a clinically used LMWH in the presence and absence of an intact endothelial glycocalyx. We show that both exogenous enzymatic degradation as well as endogenous genetic modification of the endothelial glycocalyx decreased pulmonary tumor formation in a murine experimental metastasis model. Moreover, LMWH administration significantly reduced the number of pulmonary tumor foci and thus experimental metastasis both in the presence or absence of an intact endothelial glycocalyx.ConclusionsIn summary, this paper shows that the net effect of the endothelial glycocalyx enhances experimental metastasis and that a LMWH does not limit experimental metastasis by a process involving the endothelial glycocalyx.

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Long‐term thrombin inhibition promotes cancer cell extravasation in a mouse model of experimental metastasis

Abstract: 1595-7.

Cited by 15 publications

References 13 publications

A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models

A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models

Antimetastatic activities of heparins and modified heparins. Experimental evidence

A Low Molecular Weight Heparin Inhibits Experimental Metastasis in Mice Independently of the Endothelial Glycocalyx

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