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

被引:47
作者
Feinauer, Manuel J. [1 ,2 ,3 ]
Schneider, Stefan W. [4 ]
Berghoff, Anna S. [1 ,2 ,3 ,5 ]
Robador, Jose Ramon [4 ]
Tehranian, Cedric [1 ,2 ,3 ]
Karreman, Matthia A. [1 ,2 ,3 ]
Venkataramani, Varun [1 ,2 ,3 ,6 ]
Solecki, Gergely [1 ,2 ,3 ,7 ]
Grosch, Julia Katharina [1 ,2 ,3 ]
Gunkel, Katharina [1 ,2 ,3 ]
Kovalchuk, Bogdana [1 ,2 ,3 ]
Mayer, Frank Thomas [8 ]
Fischer, Manuel [9 ]
Breckwoldt, Michael O. [9 ]
Brune, Maik [10 ]
Schwab, Yannick [11 ,12 ]
Wick, Wolfgang [1 ,2 ,3 ]
Bauer, Alexander T. [4 ]
Winkler, Frank [1 ,2 ,3 ]
机构
[1] Univ Hosp Heidelberg, Neurol Clin, Neuenheimer Feld 400, D-69120 Heidelberg, Germany
[2] Univ Hosp Heidelberg, Natl Ctr Tumor Dis, Neuenheimer Feld 400, D-69120 Heidelberg, Germany
[3] German Canc Res Ctr, Clin Cooperat Unit Neurooncol, German Canc Consortium, Heidelberg, Germany
[4] Univ Hosp Hamburg Eppendorf, Dept Dermatol & Venereol, Hamburg, Germany
[5] Med Univ Vienna, Dept Med 1, Div Oncol, Vienna, Austria
[6] Heidelberg Univ, Inst Anat & Cell Biol, Dept Funct Neuroanat, Heidelberg, Germany
[7] Carl Zeiss Microscopy GmbH, Business Unit Serv & Customer Care, Jena, Germany
[8] Heidelberg Univ, Med Fac Mannheim, Dept Dermatol & Venereol, Mannheim, Germany
[9] Heidelberg Univ Hosp, Dept Neuroradiol, Heidelberg, Germany
[10] Med Univ Hosp, Dept Endocrinol & Clin Chem, Heidelberg, Germany
[11] European Mol Biol Lab, Cell Biol & Biophys Unit, Heidelberg, Germany
[12] European Mol Biol Lab, Electron Microscopy Core Facil, Heidelberg, Germany
关键词
D O I
10.1182/blood.2020005710
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 similar to 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.
引用
收藏
页码:1219 / 1232
页数:14
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