Research and Practice in Thrombosis and Haemostasis (Jul 2024)

Modeling cancer-associated hypercoagulability using glioblastoma spheroids in microfluidic chips

  • Maaike Y. Kapteijn,
  • Monika Yanovska,
  • El Houari Laghmani,
  • Rudmer J. Postma,
  • Vincent van Duinen,
  • Betül Ünlü,
  • Karla Queiroz,
  • Anton Jan van Zonneveld,
  • Henri H. Versteeg,
  • Araci M.R. Rondon

Journal volume & issue
Vol. 8, no. 5
p. 102475

Abstract

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Background: Cancer increases the risk of venous thromboembolism, and glioblastoma is one of the cancer types with the highest risk of venous thromboembolism (10%-30%). Tumor-intrinsic features are believed to affect vascular permeability and hypercoagulability, but novel models are required to study the pathophysiological dynamics underlying cancer-associated thrombosis at the molecular level. Objectives: We have developed a novel cancer-on-a-chip model to examine the effects of glioblastoma cells on the deregulation of blood coagulation. Methods: This was accomplished by coculturing vessel-forming human umbilical vein endothelial cells with glioblastoma spheroids overexpressing tissue factor (TF), the initiator of coagulation (U251 lentivirus, LV-TF) or an LV-control (U251 LV-Ctrl) in an OrganoPlate Graft platform. Results: Using a modified thrombin generation assay inside the cancer-on-a-chip, we found that U251 LV-Ctrl and U251 LV-TF spheroids promoted an increased procoagulant state in plasma, as was shown by a 3.1- and 7.0-fold increase in endogenous thrombin potential, respectively. Furthermore, the anticoagulant drug rivaroxaban and TF coagulation-blocking antibody 5G9 inhibited the activation of blood coagulation in U251 LV-TF spheroid-containing graft plates, as was shown by a reduced endogenous thrombin potential (4.0- and 4.4-fold, respectively). Conclusion: With this study, we present a novel 3-dimensional cancer-on-a-chip model that has the potential to be used in the discovery of new anticoagulant drugs and identification of optimal anticoagulant strategies for glioblastoma and other cancer types.

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