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Journal ArticleDOI: 10.1182/BLOOD.2020005710

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

04 Mar 2021-Blood (American Society of Hematology)-Vol. 137, Iss: 9, pp 1219-1232
Abstract: 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.

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Topics: Brain metastasis (57%), Cancer (55%), Cancer cell (55%) ... read more
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6 results found


Open accessJournal ArticleDOI: 10.3390/CANCERS13081897
Julian Taranda1, Sevin Turcan1Institutions (1)
15 Apr 2021-Cancers
Abstract: Although our understanding of the two-dimensional state of brain tumors has greatly expanded, relatively little is known about their spatial structures. The interactions between tumor cells and the tumor microenvironment (TME) occur in a three-dimensional (3D) space. This volumetric distribution is important for elucidating tumor biology and predicting and monitoring response to therapy. While static 2D imaging modalities have been critical to our understanding of these tumors, studies using 3D imaging modalities are needed to understand how malignant cells co-opt the host brain. Here we summarize the preclinical utility of in vivo imaging using two-photon microscopy in brain tumors and present ex vivo approaches (light-sheet fluorescence microscopy and serial two-photon tomography) and highlight their current and potential utility in neuro-oncology using data from solid tumors or pathological brain as examples.

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Topics: Preclinical imaging (55%)

1 Citations


Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.723905
Xiaoye Li1, Xiaochun Zhang1, Qinchun Jin1, Yanli Li1  +3 moreInstitutions (1)
Abstract: Background: The current post-procedure antithrombotic recommendation for left atrial appendage closure (LAAC) remains empiric. This study was designed to compare variations in platelet activation biomarkers and device-related thrombosis (DRT) under different antithrombotic regimens following LAAC. Methods: This study enrolled 105 consecutive patients with atrial fibrillation who underwent LAAC successfully and received post-procedure anticoagulation with either dabigatran (N = 33) or rivaroxaban (N = 72). After 3 months of anticoagulation treatment, thromboelastogram was used to evaluate thrombin receptor-activating peptide (TRAP)-induced platelet aggregation (PA). Measurements of platelet activation biomarkers, including thrombin-antithrombin complex (TAT), P-selectin, von Willebrand disease (vWF), and CD40L, were performed immediately before the LAAC procedure and after 3 months of post-procedure anticoagulation. Repeated transesophageal echocardiography was performed to evaluate DRT during follow-ups. Results: Three (4.2%) patients in the rivaroxaban and 4 (12.1%) patients in the dabigatran group experienced DRT events (odds ratio (OR) = 0.315, 95% confidence interval (95%CI): 0.066-1.489, p = 0.129) during follow-ups. The TRAP-induced PA was statistically significantly higher in the dabigatran group (62.9% vs 59.7%, p = 0.028*). Statistically significant increases in plasma concentration of TAT, P-selectin, and vWF were observed after 3 months of exposure to dabigatran when compared with rivaroxaban. An increased expression of platelet activation biomarkers was observed in DRT subjects compared with non-DRT subjects in terms of P-selectin and vWF (65.28 ± 13.93 ng/L vs 32.14 ± 12.11 ng/L, p = 0.037; 501.92 ± 106.48 U/L vs 280.98 ± 54.10 U/L, p = 0.045; respectively). Multivariate regression analysis indicated that the use of dabigatran might be an independent predictor of DRT (p = 0.022; OR = 4.366, 95%CI: 0.434-10.839). Furthermore, the CHA2DS2-VASc score (OR = 2.076, p = 0.016) and CD40L levels (OR = 1.015, p = 0.021) were independent predictors of increased D-dimer levels. Conclusions: Post-LAAC anticoagulation with dabigatran may increase the risk of DRT by enhancing platelet reactivity. In light of this potential increased risk in DRT, the authors recommend against using dabigatran for post-procedural anticoagulation in patients who have undergone LAAC.

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Topics: Platelet activation (58%), Dabigatran (54%), Rivaroxaban (50%)

Open accessJournal ArticleDOI: 10.1182/BLOOD.2020010130
Gregory J. del Zoppo1, Yu-Huan Gu1Institutions (1)
04 Mar 2021-Blood
Abstract: In this issue of Blood, Feinauer et al focus on central nervous system (CNS) metastases generated by embolization of tumor cells into the cortical capillary network in a mouse model, and early thrombotic events that might facilitate metastasis.

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Open accessJournal ArticleDOI: 10.3390/CELLS10092351
Angelika Mojzisch1, Maria A. Brehm2Institutions (2)
08 Sep 2021-Cells
Abstract: The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a “fishing hook” for platelets and a transporter for coagulation factor VIII. VWF is a true multitasker when it comes to its many roles in cellular processes. In ECs, VWF coordinates the formation of Weibel–Palade bodies and guides several cargo proteins to these storage organelles, which control the release of hemostatic, inflammatory and angiogenic factors. Leukocytes employ VWF to assist their rolling on, adhesion to and passage through the endothelium. Vascular smooth muscle cell proliferation is supported by VWF, and it regulates angiogenesis. The life cycle of platelets is accompanied by VWF from their budding from megakaryocytes to adhesion, activation and aggregation until the end in apoptosis. Some tumor cells acquire the ability to produce VWF to promote metastasis and hide in a shell of VWF and platelets, and even the maturation of osteoclasts is regulated by VWF. This review summarizes the current knowledge on VWF’s versatile cellular functions and the resulting pathophysiological consequences of their dysregulation.

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Topics: Platelet (53%), Coagulation (53%), Von Willebrand factor (52%)

Open accessDOI: 10.1093/NOAJNL/VDAB121
Ethan S Srinivasan1, Krutika Deshpande2, Josh Neman2, Frank Winkler3  +2 moreInstitutions (4)
27 Nov 2021-
Abstract: Brain metastasis (BrM) is an area of unmet medical need that poses unique therapeutic challenges and heralds a dismal prognosis. The intracranial tumor microenvironment (TME) presents several challenges, including the therapy-resistant blood-brain barrier, a unique immune milieu, distinct intercellular interactions, and specific metabolic conditions, that are responsible for treatment failures and poor clinical outcomes. There is a complex interplay between malignant cells that metastasize to the central nervous system (CNS) and the native TME. Cancer cells take advantage of vascular, neuronal, immune, and anatomical vulnerabilities to proliferate with mechanisms specific to the CNS. In this review, we discuss unique aspects of the TME in the context of brain metastases and pathways through which the TME may hold the key to the discovery of new and effective therapies for patients with BrM.

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References
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50 results found


Open accessJournal ArticleDOI: 10.1038/NMETH.2019
01 Jul 2012-Nature Methods
Abstract: Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.

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Topics: Software design (51%), Software (50%)

30,888 Citations


Open accessJournal ArticleDOI: 10.1038/S41598-017-17204-5
04 Dec 2017-Scientific Reports
Abstract: QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.

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Topics: Digital pathology (58%), Image processing (50%)

1,303 Citations


Open accessJournal ArticleDOI: 10.1038/NRC3004
Brunhilde Felding-Habermann1Institutions (1)
Abstract: Experimental evidence suggests that platelets contribute to metastasis through adhesive and haemostatic functions that promote cancer cell survival, immune evasion and interactions with vascular cells to assist organ colonization from the bloodstream. Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.

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Topics: Metastasis (53%), Cancer cell (52%), Platelet (51%)

1,096 Citations


Journal ArticleDOI: 10.1038/NM.2072
01 Jan 2010-Nature Medicine
Abstract: Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.

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Topics: Brain metastasis (57%), Cancer (55%), Angiogenesis (55%) ... read more

836 Citations


Journal ArticleDOI: 10.1038/NM782
16 Sep 2002-Nature Medicine
Abstract: We have used confocal and widefield microscopy to image thrombus formation in real time in the microcirculation of a living mouse. This system provides high-speed, near-simultaneous acquisition of images of multiple fluorescent probes and of a brightfield channel. Vascular injury is induced with a laser focused through the microscope optics. We observed platelet deposition, tissue factor accumulation and fibrin generation after laser-induced endothelial injury in a single developing thrombus. The initiation of blood coagulation in vivo entailed the initial accumulation of tissue factor on the upstream and thrombus–vessel wall interface of the developing thrombus. Subsequently tissue factor was associated with the interior of the thrombus. Tissue factor was biologically active, and was associated with fibrin generation within the thrombus.

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Topics: Thrombus (65%), Tissue factor (55%), Fibrin (53%) ... read more

629 Citations


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