Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation

Abstract

Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model.

Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement

“…2,3 Interventions with direct or indirect thrombin inhibitors, ie, hirudin and low molecular weight heparin, respectively, inhibit experimental metastasis. [35][36][37][38] Besides, congenital susceptibility to either bleeding or thrombosis modifies the metastatic capacity of some types of cancer cells 23 but not others 39 in the blood stream. Hemophilic (factor VIII deficient) mice were protected against melanoma lung metastasis, whereas thrombophilic factor V Leiden mice developed more metastases than did wild-type littermates.…”

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

“…The congenital coagulation disorder FV Leiden (FVL) promotes melanoma tumor development in mouse lung, whereas FVIII-deficient (haemophilic) mice are protected against melanoma tumor growth in lungs indicating a role for the coagulation process [15]. However, a lack of effects of FVL has been observed as well in colon cancer tumor development in mouse liver [16] indicating that the coagulation system is not effective in all organs. Moreover, not all anticoagulants are effective inhibitors of cancer progression [17][18][19].…”

Protease-Activated Receptors, Apoptosis and Tumor Growth

“…Drs Trousseau and Bouillaud already described the association between cancer and venous thrombosis during the 1800s and malignancy related thromboembolism is consequently known as Trousseau's syndrome [14] . The fact that several studies show that anticoagulant therapy improves survival of cancer patients [15][16][17] indicates that thrombosis is not just an epiphenomenon of underlying cancer, but that individual factors of the coagulation cascade actively participate in the progression of cancer and are detrimental for the outcome of the disease. Strikingly, many tumor cells bear constitutively active TF on their surface, which activates the coagulation cascade leading to thrombin generation, and enzymatically active thrombin is present on surgically removed tumor specimens [18] .…”