Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model.

Autor:	Feinauer MJ; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Schneider SW; Department of Dermatology and Venereology, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Berghoff AS; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.; Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria., Robador JR; Department of Dermatology and Venereology, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Tehranian C; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Karreman MA; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Venkataramani V; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Solecki G; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.; Business Unit Service and Customer Care, Carl Zeiss Microscopy GmbH, Jena, Germany., Grosch JK; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Gunkel K; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Kovalchuk B; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Mayer FT; Department of Dermatology and Venereology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Fischer M; Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany., Breckwoldt MO; Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany., Brune M; Department of Endocrinology and Clinical Chemistry, Medical University Hospital, Heidelberg, Germany; and., Schwab Y; Cell Biology and Biophysics Unit, and Electron Microscopy Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany., Wick W; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany., Bauer AT; Department of Dermatology and Venereology, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Winkler F; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Mar 04; Vol. 137 (9), pp. 1219-1232.
DOI:	10.1182/blood.2020005710
Abstrakt:	Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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