Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model
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Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model. / Feinauer, Manuel J; Schneider, Stefan W; Berghoff, Anna Sophie; Robador, Jose Ramon; Tehranian, Cedric; Karreman, Matthia A; Venkataramani, Varun; Solecki, Gergely; Grosch, Julia Katharina; Gunkel, Katharina; Kovalchuk, Bogdana; Mayer, Frank Thomas; Fischer, Manuel; Breckwoldt, Michael O; Brune, Maik; Schwab, Yannik; Wick, Wolfgang; Bauer, Alexander Thomas; Winkler, Frank.
In: BLOOD, Vol. 137, No. 9, 04.03.2021, p. 1219-1232.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model
AU - Feinauer, Manuel J
AU - Schneider, Stefan W
AU - Berghoff, Anna Sophie
AU - Robador, Jose Ramon
AU - Tehranian, Cedric
AU - Karreman, Matthia A
AU - Venkataramani, Varun
AU - Solecki, Gergely
AU - Grosch, Julia Katharina
AU - Gunkel, Katharina
AU - Kovalchuk, Bogdana
AU - Mayer, Frank Thomas
AU - Fischer, Manuel
AU - Breckwoldt, Michael O
AU - Brune, Maik
AU - Schwab, Yannik
AU - Wick, Wolfgang
AU - Bauer, Alexander Thomas
AU - Winkler, Frank
N1 - Copyright © 2020 American Society of Hematology.
PY - 2021/3/4
Y1 - 2021/3/4
N2 - 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.
AB - 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.
U2 - 10.1182/blood.2020005710
DO - 10.1182/blood.2020005710
M3 - SCORING: Journal article
C2 - 33270819
VL - 137
SP - 1219
EP - 1232
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 9
ER -
