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.
Highlights
Thrombotic complications are among the leading causes of morbidity and mortality in cancer patients[1,2] and to date, low molecular weight heparin (LMWH) remains a recommended regime for anticoagulation in cancer patients[2,3,4]
The chorioallantoic membrane assay (CAM) were supplemented with the LMWH; Tinzaparin and Dalteparin, and with direct oral anti-coagulants; Apixaban and Rivaroxaban, and were compared to the effects of the VEGF-receptor blocker; Bevacizumab, in vivo
The inclusion of Rivaroxaban or Apixaban did not have any detectable influence on tumour invasiveness in WM-266-4 (Fig. 2) or AsPC-1 cells
Summary
Thrombotic complications are among the leading causes of morbidity and mortality in cancer patients[1,2] and to date, low molecular weight heparin (LMWH) remains a recommended regime for anticoagulation in cancer patients[2,3,4]. Favourable biological effects of LMWH in the treatment of cancer patients appear to extend beyond the treatment of thrombosis[5,6,7] these have not definitively translated into clinical gains[8,9] These beneficial influences include the inhibition of chemotaxis[10,11], tumour growth[10,12], metastasis[5,10,13,14] and the inhibition of angiogenesis[14,15,16,17,18,19], and are not mutually exclusive. The anticoagulant function of agents such as Apixaban and Rivaroxaban is derived from the inhibition of coagulation factor Xa, and is similar to that of a number of LMWH These agents do not require the function of antithrombin III, which possesses independent anti-angiogenic properties[29]. The direct influence of these anticoagulants on tumour formation, growth and invasion was examined by preparing spheroid tumours which were implanted into the invasion matrix in vitro
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