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Tumor Microenvironment and Immunobiology

Urothelial Carcinoma of the Bladder Induces Endothelial Cell Activation and Hypercoagulation

Axel John, José R. Robador, Sabine Vidal-y-Sy, Pia Houdek, Ewa Wladykowski, Cagatay Günes, Christian Bolenz, Stefan W. Schneider, Alexander T. Bauer and Christian Gorzelanny
Axel John
1Department of Urology, University of Ulm, Ulm, Germany.
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José R. Robador
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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  • ORCID record for José R. Robador
Sabine Vidal-y-Sy
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Pia Houdek
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Ewa Wladykowski
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Cagatay Günes
1Department of Urology, University of Ulm, Ulm, Germany.
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Christian Bolenz
1Department of Urology, University of Ulm, Ulm, Germany.
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Stefan W. Schneider
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Alexander T. Bauer
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Christian Gorzelanny
2Experimental Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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  • ORCID record for Christian Gorzelanny
  • For correspondence: c.gorzelanny@uke.de
DOI: 10.1158/1541-7786.MCR-19-1041 Published July 2020
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Abstract

Cancer-related venous thromboembolisms (VTE) are associated with metastasis and reduced survival in patients with urothelial cancer of the bladder. Although previous reports suggest the contribution of tissue factor and podoplanin, the mechanistic linkage between VTE and bladder cancer cell–derived molecules is unknown. Therefore, we compared distinct procoagulant pathways in four different cell lines. In vitro findings were further confirmed by microfluidic experiments mimicking the pathophysiology of tumor blood vessels and in tissue samples of patients with bladder cancer by transcriptome analysis and immunohistology. In vitro and microfluidic experiments identified bladder cancer–derived VEGF-A as highly procoagulant because it promoted the release of von Willebrand factor (VWF) from endothelial cells and thus platelet aggregation. In tissue sections from patients with bladder cancer, we found that VWF-mediated blood vessel occlusions were associated with a poor outcome. Transcriptome data further indicate that elevated expression levels of enzymes modulating VEGF-A availability were significantly connected to a decreased survival in patients with bladder cancer. In comparison with previously postulated molecular players, we identified tumor cell–derived VEGF-A and endothelial VWF as procoagulant mediators in bladder cancer. Therapeutic strategies that prevent the VEGF-A–mediated release of VWF may reduce tumor-associated hypercoagulation and metastasis in patients with bladder cancer.

Implications: We identified the VEGF-A–mediated release of VWF from endothelial cells to be associated with bladder cancer progression.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1099–109

  • Received October 21, 2019.
  • Revision received January 15, 2020.
  • Accepted March 26, 2020.
  • Published first March 31, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (7)
July 2020
Volume 18, Issue 7
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Urothelial Carcinoma of the Bladder Induces Endothelial Cell Activation and Hypercoagulation
Axel John, José R. Robador, Sabine Vidal-y-Sy, Pia Houdek, Ewa Wladykowski, Cagatay Günes, Christian Bolenz, Stefan W. Schneider, Alexander T. Bauer and Christian Gorzelanny
Mol Cancer Res July 1 2020 (18) (7) 1099-1109; DOI: 10.1158/1541-7786.MCR-19-1041

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Urothelial Carcinoma of the Bladder Induces Endothelial Cell Activation and Hypercoagulation
Axel John, José R. Robador, Sabine Vidal-y-Sy, Pia Houdek, Ewa Wladykowski, Cagatay Günes, Christian Bolenz, Stefan W. Schneider, Alexander T. Bauer and Christian Gorzelanny
Mol Cancer Res July 1 2020 (18) (7) 1099-1109; DOI: 10.1158/1541-7786.MCR-19-1041
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