gms | German Medical Science

Objective: Vascular endothelial cell (EC) activation by tumor cells might promote tumor cell homing and tumor-related hypercoagulopathy both leading to metastasis formation especially in the brain and venous thromboembolism, a common complication in patients with brain metastases. Our previous studies revealed that melanoma cells activate ECs followed by the luminal release of the procoagulatory protein von Willebrand factor (VWF). Using mouse melanoma tumors and tissue samples obtained from tumor patients, we demonstrate tumor cell-induced EC activation and intraluminal VWF fibers mediating platelet binding in the primary tumor. as an explanation for microthrombosis and tumor cell homing, but also the formation of perilesional micrometastases.

Method: We used different mouse models (ret transgenic mouse model; intradermal inoculation of melanoma cells), tissue samples from patients with cerebral metastases of different origin and patients with atypical meningiomas as control. EC activation, VWF distribution and platelet aggregation was examined in the microenvironment of the tumor and perilesional brain tissue using immunofluorescence studies and high resolution microscopy. Finally, the ability of the anticoagulant Tinzaparin to counteract tumor-associated VWF fiber formation and tumor progression was tested in the ret transgenic mouse model. The study was approved by the local ethic committee and all patients participated voluntarily and gave their written consent.

Results: Immunofluorescence studies of wildtype mouse brains showed VWF in the vessel wall and no VWF fibers in the lumen. In contrast brains of ret mice spontaneously developing melanoma and cerebral metastases exhibited intraluminal VWF networks, indicative for EC activation. In patients whereas almost no VWF fibers could be detected in the vasculature of perilesional brain tissue, metastatic tissue displayed a high proportion of intraluminal VWF networks. Interestingly, tumor-bearing mice (only primary tumor) lacking any metastatic foci in the brain showed a significant increase of vessels with luminal VWF strings. Even more, targeting EC activation using systemic anticoagulation with Tinzaparin in the ret transgenic mouse model VWF fiber formation and platelet aggregation was blocked.

Conclusions: Our data provide novel mechanistic insights into cancer-related thromboembolism and the tumor cell- EC axis as potential therapeutic target for drugs preventing tumor-related coagulation and metastasis.