Shibata Chikako, Otsuka Motoyuki, Ishigaki Kazunaga, Seimiya Takahiro, Kishikawa Takahiro, Fujishiro Mitsuhiro
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Gastro Hep Adv. 2024 Feb 29;3(4):551-561. doi: 10.1016/j.gastha.2024.02.005. eCollection 2024.
Cancer-associated venous thromboembolism (VTE) is a frequent complication associated with high mortality in patients with cancer, particularly pancreatic cancer. While biological factors such as coagulation factors released from cancer cells may underlie the mechanisms of cancer-associated VTE, the detailed mechanisms have not been determined. Here, we aimed to determine whether extracellular vesicles carrying a glycan sialyl-Lewis, known as carbohydrate antigen 19-9 (CA19-9), which is a clinically used serum tumor marker and selectin ligand, are a significant cause of cancer-associated VTE.
Risk factors for cancer-associated VTE were determined using clinical data. EVs derived from CA19-9-deficient or overexpressing pancreatic cancer cells were characterized. The protein levels of coagulation factors on the surface of the EVs were quantified using our newly developed sensitive method.
Higher CA19-9 levels in the sera of patients were significantly associated with the occurrence of VTE. Using CA19-9-negative or overexpressing pancreatic cancer cells, we found that EVs derived from these cells interacted with E-selectin of endothelial cells in a CA19-9-dependent manner in cell-based assays and in vitro blood vessel models. EVs derived from cancer cells have higher tissue factor levels on their surfaces, and increased tissue factor activity is induced locally, where CA19-9-positive EVs bind to activated endothelial cells.
These results suggest that the binding between CA19-9-positive EVs released from cancer cells and endothelial cell E-selectin explains the increased frequency of VTE in patients with pancreatic cancer.
癌症相关静脉血栓栓塞症（VTE）是癌症患者常见的并发症，死亡率高，尤其是胰腺癌患者。虽然癌细胞释放的凝血因子等生物学因素可能是癌症相关VTE机制的基础，但具体机制尚未确定。在此，我们旨在确定携带聚糖唾液酸路易斯（称为碳水化合物抗原19-9，CA19-9）的细胞外囊泡是否是癌症相关VTE的重要原因，CA19-9是一种临床使用的血清肿瘤标志物和选择素配体。
利用临床数据确定癌症相关VTE的危险因素。对源自CA19-9缺陷或过表达胰腺癌细胞的细胞外囊泡进行表征。使用我们新开发的灵敏方法对细胞外囊泡表面凝血因子的蛋白水平进行定量。
患者血清中较高的CA19-9水平与VTE的发生显著相关。使用CA19-9阴性或过表达的胰腺癌细胞，我们发现在基于细胞的试验和体外血管模型中，源自这些细胞的细胞外囊泡以CA19-9依赖的方式与内皮细胞的E选择素相互作用。源自癌细胞的细胞外囊泡表面具有更高的组织因子水平，并且在CA19-9阳性细胞外囊泡与活化内皮细胞结合的局部诱导组织因子活性增加。
这些结果表明，癌细胞释放的CA19-9阳性细胞外囊泡与内皮细胞E选择素之间的结合解释了胰腺癌患者VTE发生率增加的原因。
