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

Abstract

Clinically relevant brain metastases (BM) 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 are not well understood. Here, in vivo multiphoton laser-scanning microscopy (MPLSM) 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-time arrest. An extensive clot embedded approximately 20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, tissue factor-mediated thrombin generation 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 brain macrometastasis formation. 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 BM formation. In conclusion, our data shows that plasmatic coagulation is activated early by intravascular tumor cells in the brain, with subsequent clot formation, discovering a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for BM prevention trials.

The Manifold Cellular Functions of von Willebrand Factor

“…In vitro, addition of tumor secretomes of, for example, PC3 prostate cancer cells [ 164 ], melanoma cells (MV3, BLM) [ 165 , 166 ], A549 lung adenocarcinoma cells [ 167 ] and RT4 urothelial carcinoma cells [ 168 ] to ECs was observed to induce WPB secretion and thus release of VWF. In the blood stream, tumor cells can bind VWF and platelets to shield themselves from being detected by immune cells ( Figure 4 c) and to promote clot formation, as observed by Feinauer et al [ 161 ]. Here, VWF can function as an adhesive anchor for tumor cells to facilitate docking to the endothelium and subsequent extravasation ( Figure 4 d,e).…”

“…Additionally, tumor cell survival in the perivascular niche was reduced in the breast cancer model in the presence of anti-VWF antibodies. Here again, the VWF–integrin interaction could come into play [ 161 ]. Extravasation could be further promoted by neutrophils which were shown to be recruited by VWF fibers ( Figure 4 a) [ 127 , 162 ].…”

Dabigatran Treatment Increased Closure Device-Related Thrombosis by Platelet Activation in Patients Undergoing Percutaneous Left Atrial Appendage Closure

“…In the present study, administration with dabigatran displayed an increasing expression of plasma vWF. The probable reason might be that dabigatran anticoagulation was associated with in ammation, endothelial dysfunction, and oxidative stress, increased expression of angiogenic and cell adhesion molecules [29].…”

Breast-to-brain metastasis: a focus on the pre-metastatic niche

“…The neutrophil-like CD11b + Gr1 + myeloid cells promote the formation of a premetastatic niche within the brain through secretion of proinflammatory cytokines, such as S100A8, S100A9, and SAA3 [126,127] . Activated neutrophils release S100A8 and S100A9, which form heterodimers to support this mechanism across systems [128] . Once the initial metastatic niche has been formed, additional immunosuppressive neutrophils are recruited through the function of phosphorylated EZH2 [124] .…”