gms | German Medical Science

Objective: Venous thromboembolism is a frequent complication in cancer patients with brain metastases. Although anticoagulation revealed therapeutic effects, the impact of the coagulation on brain metastasis formation remains elusive. Own studies based on a mouse model of hematogenous lung seeding in malignant melanoma identified hallmarks of tumor-associated thrombosis in lungs, including von Willebrand factor (VWF) fibers and thrombotic vessel occlusions. Treatment with low molecular weight heparins (LMWHs) inhibited VWF network formation and lung metastases. Thus, we postulate that VWF fibers contribute to cancer-associated hypercoagulation and the formation of metastatic lesions in the brain.

Methods: Cell-based assays were used to examine the molecular mechanisms of melanoma-mediated activation of brain microvascular endothelial cells (BMECs) with subsequent VWF release. Different anticoagulant heparins were screened for their capacities to block tumor-induced EC activation, permeability and transmigration of tumor cells using a model of the blood-brain-barrier (BBB). Mouse models and tissue samples from patients with cerebral metastases were used to evaluate whether VWF affects cancer-associated thrombosis in the brain. The study was approved by the local ethic committee and all patients participated voluntarily and gave their written consent.

Results: In vitro settings showed that microvascular ECs express VWF to lesser extent compared to macrovascular ECs, but are able to deposit VWF fibers on the luminal surface upon activation by tumor cells. In contrast to Fondaparinux additional inhibition of VEGF-A by the LMWH Tinzaparin blocked tumor cell-mediated EC activation, luminal VWF fiber formation, permeability and extravasation of tumour cells in an in vitro model of the BBB. Taken advantage of the ret transgenic mouse model, characterized by spontaneous formation of brain metastases, and human tissue sections confirmed the in vivo relevance of intraluminal VWF networks. Notably, intradermal melanoma cell injection was sufficient to induce VWF-platelet aggregates and thrombotic vessel occlusions distal from the primary tumor and thus revealed pre-metastatic niches in early tumour stages. Finally, inhibition of thrombin and VEGF-A with Tinzaparin inhibited VWF network formation and platelet aggregation in the microvasculature of ret mouse brains reflected by a survival benefit and a strong trend towards reduced brain metastases.

Conclusion: Our data support a critical role of VWF fibers in malignancy-associated thrombosis and intracranial metastases. Non-anticoagulant activities of LMWHs provide the basis for the development of innovative anti-metastatic strategies.