Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism
Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism
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阻断VCAM-1可抑制胰腺肿瘤进展和癌症相关血栓形成/血栓栓塞
DOI：
10.1136/gutjnl-2020-320608
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发表时间：
2021-09-01
期刊：
影响因子：
24.5
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Sano, Makoto;Takahashi, Ryota;Koike, Kazuhiko
目的胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是最致命的肿瘤。癌症相关血栓形成/血栓栓塞（CAT），在PDAC中经常观察到，被认为是一个不良预后因素。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 (Ptf1a(cre/+);LSL-Kras（G12D/+);Tgfbr2(flox/flox)）进行了PDAC治疗方法的试验。设计通过全身解剖检测PKF小鼠中CAT的存在。采用细胞因子抗体阵列法筛选血浆细胞因子。采用ELISA法测定小鼠和人血浆心房钠肽（ANP）和可溶性血管细胞粘附分子1 （sVCAM-1）的含量。免疫组织化学检测VCAM-1在PKF小鼠和人体解剖样本中的分布。用抗vcam -1抗体治疗PKF小鼠，分析其对小鼠生存、CAT分布及肿瘤组织学的影响。结果68.4%的PKF小鼠出现自发性CAT伴心脏增大。PKF小鼠和PDAC伴CAT患者血浆ANP和sVCAM-1升高。在活化的内皮细胞和血栓中检测到VCAM-1。给PKF小鼠抗vcam -1抗体抑制肿瘤生长、中性粒细胞/巨噬细胞浸润、肿瘤血管生成和CAT进展；此外，它显著延长了生存期(从61天延长到253天，p
Objective 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 (Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox)).Design 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.Results 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