gms | German Medical Science

67th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Korean Neurosurgical Society (KNS)

German Society of Neurosurgery (DGNC)

12 - 15 June 2016, Frankfurt am Main

The role of intracranial endothelial cell activation in peritumoral micrometastasis formation and thrombosis – a first approach

Meeting Abstract

  • Marcel Seiz-Rosenhagen - Neurochirurgische Klinik, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
  • Daniel Haenggi - Neurochirurgische Klinik, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
  • Thomas Mayer - Abteilung für experimentelle Dermatologie, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
  • Jose Robador - Abteilung für experimentelle Dermatologie, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
  • Stefan W. Schneider - Abteilung für experimentelle Dermatologie, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
  • Alexander T. Bauer - Abteilung für experimentelle Dermatologie, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocMI.10.09

doi: 10.3205/16dgnc290, urn:nbn:de:0183-16dgnc2909

Published: June 8, 2016

© 2016 Seiz-Rosenhagen et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

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.