Kapteijn Maaike Y, Yanovska Monika, Laghmani El Houari, Postma Rudmer J, van Duinen Vincent, Ünlü Betül, Queiroz Karla, van Zonneveld Anton Jan, Versteeg Henri H, Rondon Araci M R
Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Division of Nephrology, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Res Pract Thromb Haemost. 2024 Jun 17;8(5):102475. doi: 10.1016/j.rpth.2024.102475. eCollection 2024 Jul.
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.
We have developed a novel cancer-on-a-chip model to examine the effects of glioblastoma cells on the deregulation of blood coagulation.
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.
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).
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.
癌症会增加静脉血栓栓塞的风险，胶质母细胞瘤是静脉血栓栓塞风险最高的癌症类型之一（10%-30%）。肿瘤内在特征被认为会影响血管通透性和高凝状态，但需要新的模型来在分子水平研究癌症相关血栓形成的病理生理动力学。
我们开发了一种新型的芯片上癌症模型，以研究胶质母细胞瘤细胞对凝血失调 的影响。
通过在OrganoPlate Graft平台上，将形成血管的人脐静脉内皮细胞与过表达凝血启动因子组织因子（TF）的胶质母细胞瘤球体（U251慢病毒，LV-TF）或LV对照（U251 LV-Ctrl）共培养来实现。
在芯片上癌症模型中使用改良的凝血酶生成试验，我们发现U251 LV-Ctrl和U251 LV-TF球体均促进血浆中促凝状态增加，内源性凝血酶潜力分别增加3.1倍和7.0倍。此外，抗凝药物利伐沙班和TF凝血阻断抗体5G9抑制了含U251 LV-TF球体的移植板中的凝血激活，内源性凝血酶潜力降低（分别为4.0倍和4.4倍）。
通过本研究，我们提出了一种新型的三维芯片上癌症模型，该模型有潜力用于发现新的抗凝药物以及确定胶质母细胞瘤和其他癌症类型的最佳抗凝策略。
