Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Division of Medical Research Planning and Development, Nihon University School of Medicine, Tokyo, Japan.
Gut. 2021 Sep;70(9):1713-1723. doi: 10.1136/gutjnl-2020-320608. Epub 2020 Oct 21.
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer. Cancer-associated thrombosis/thromboembolism (CAT), frequently observed in PDAC, is known as a poor prognostic factor. Here, we investigated the underlying mechanisms between PDAC and CAT, and performed a trial of therapeutic approach for PDAC using a genetically engineered mouse model, PKF ( ).
Presence of CAT in PKF mice was detected by systemic autopsy. Plasma cytokines were screened by cytokine antibody array. Murine and human plasma atrial natriuretic peptide (ANP) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were determined by ELISA. Distribution of VCAM-1 in PKF mice and human autopsy samples was detected by immunohistochemistry. PKF mice were treated with anti-VCAM-1 antibody and the effects on survival, distribution of CAT and the tumour histology were analysed.
We found spontaneous CAT with cardiomegaly in 68.4% PKF mice. Increase of plasma ANP and sVCAM-1 was observed in PKF mice and PDAC patients with CAT. VCAM-1 was detected in the activated endothelium and thrombi. Administration of anti-VCAM-1 antibody to PKF mice inhibited tumour growth, neutrophil/macrophage infiltration, tumour angiogenesis and progression of CAT; moreover, it dramatically extended survival (from 61 to 253 days, p<0.01).
Blocking VCAM-1/sVCAM-1 might be a potent therapeutic approach for PDAC as well as CAT, which can contribute to the prognosis. Increase of plasma ANP and sVCAM-1 might be a diagnostic approach for CAT in PDAC.
胰腺导管腺癌（PDAC）是最致命的癌症。在 PDAC 中经常观察到的癌症相关血栓形成/血栓栓塞（CAT）是预后不良的因素。在这里，我们研究了 PDAC 和 CAT 之间的潜在机制，并使用基因工程小鼠模型 PKF（）进行了 PDAC 治疗方法的试验。
通过系统尸检检测 PKF 小鼠中 CAT 的存在。通过细胞因子抗体阵列筛选血浆细胞因子。通过 ELISA 测定鼠和人血浆心钠肽（ANP）和可溶性血管细胞黏附分子 1（sVCAM-1）。通过免疫组织化学检测 PKF 小鼠和人尸检样本中 VCAM-1 的分布。用抗 VCAM-1 抗体治疗 PKF 小鼠，分析其对生存、CAT 分布和肿瘤组织学的影响。
我们发现 68.4%的 PKF 小鼠自发发生 CAT，伴有心脏肿大。PKF 小鼠和伴有 CAT 的 PDAC 患者的血浆 ANP 和 sVCAM-1 增加。VCAM-1 存在于活化的内皮细胞和血栓中。向 PKF 小鼠施用抗 VCAM-1 抗体可抑制肿瘤生长、中性粒细胞/巨噬细胞浸润、肿瘤血管生成和 CAT 进展；此外，还可显著延长生存时间（从 61 天延长至 253 天，p<0.01）。
阻断 VCAM-1/sVCAM-1 可能是 PDAC 以及 CAT 的有效治疗方法，有助于改善预后。血浆 ANP 和 sVCAM-1 的增加可能是 PDAC 中 CAT 的诊断方法。
