Low molecular weight heparin and direct oral anticoagulants influence tumour formation, growth, invasion and vascularisation by separate mechanisms

Featherby, Sophie; Xiao, Yu Pei; Ettelaie, Camille; Nikitenko, Leonid L.; Greenman, John; Maraveyas, Anthony

Abstract

The bidirectional association between coagulation and cancer has been established. However, anticoagulant therapies have been reported to have beneficial outcomes by influencing the vascularisation of the tumours. In this study the influence of a set of anticoagulants on tumour formation, invasion and vascularisation was examined. WM-266-4 melanoma and AsPC-1 pancreatic cancer cell lines were treated with LMWH (Tinzaparin and Dalteparin), and DOAC (Apixaban and Rivaroxaban) and the rate of tumour formation, growth and invasion were measured in vitro. In addition, the influence of these anticoagulants on vascularisation was examined using the chorioallantoic membrane assay (CAM) model and compared to the outcome of treatment with Bevacizumab. Using this model the influence of pharmacological concentrations of the anticoagulant on the growth, invasion and vascularisation of tumours derived from WM-266-4 and AsPC-1 cells was also measured in vivo. Tinzaparin and Daltepain reduced tumour formation and invasion by the cell lines in vitro, but with dissimilar potencies. In addition, treatment of CAM with LMWH reduced the local vascular density beyond that achievable with Bevacizumab, particularly suppressing the formation of larger-diameter blood vessels. In contrast, treatment with DOAC was largely ineffective. Treatment of CAM-implanted tumours with LMWH also reduced tumour vascularisation, while treatment of tumours with Apixaban reduced tumour growth in vivo. In conclusion, LMWH and DOAC appear to have anti-cancer properties that are exerted through different mechanisms.

Citation

Featherby, S., Xiao, Y. P., Ettelaie, C., Nikitenko, L. L., Greenman, J., & Maraveyas, A. (2019). Low molecular weight heparin and direct oral anticoagulants influence tumour formation, growth, invasion and vascularisation by separate mechanisms. Scientific reports, 9(1), Article 6272. https://doi.org/10.1038/s41598-019-42738-1

• Journal Article Type: Article
• Acceptance Date: Apr 5, 2019
• Online Publication Date: Apr 18, 2019
• Publication Date: 2019-12
• Deposit Date: May 15, 2019
• Publicly Available Date: May 15, 2019
• Journal: Scientific Reports
• Print ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 1
• Article Number: 6272
• DOI: https://doi.org/10.1038/s41598-019-42738-1
• Keywords: Cell invasion; Drug development; Tumour angiogenesis
• Public URL: https://hull-repository.worktribe.com/output/1624404
• Publisher URL: https://www.nature.com/articles/s41598-019-42738-1
• Additional Information: Received: 16 November 2018; Accepted: 5 April 2019; First Online: 18 April 2019; : The authors declare no competing interests.
• Contract Date: May 15, 2019