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 (Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/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<0.01).
Conclusion 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.
- pancreatic cancer
- cell adhesion molecules
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MS and RT contributed equally.
Correction notice This article has been corrected since it published Online First. The author name, Jinsuk Kim, has been corrected.
Contributors MS, RT, HIj and SM designed experiments. MS and RT acquired and analysed data. MS, RT and HIj wrote the manuscript. TY, KM, GK and JK performed a part of experiments. KI, SM, YN and HIs provided clinical concept. YMa, YMo, MT and TU supported pathological analysis. KM, HK, HF, TN, YT, KT and YI discussed data and provided intellectual input. HLM reviewed the manuscript and KK supervised the study.
Funding This work was supported by the Japanese Society for the Promotion of Science Kakenhi Grant 26430107 and 17K07155, and the Fugaku Trust for Medicinal Research.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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