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Original research
Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism
  1. Makoto Sano1,2,
  2. Ryota Takahashi1,
  3. Hideaki Ijichi1,3,
  4. Kazunaga Ishigaki1,
  5. Tomoharu Yamada1,
  6. Koji Miyabayashi1,
  7. Gen Kimura1,
  8. Suguru Mizuno1,
  9. Hiroyuki Kato1,
  10. Hiroaki Fujiwara1,
  11. Takuma Nakatsuka1,
  12. Yasuo Tanaka1,
  13. Jinsuku Kim2,
  14. Yohei Masugi4,
  15. Yasuyuki Morishita5,
  16. Mariko Tanaka5,
  17. Tetsuo Ushiku5,
  18. Yousuke Nakai1,6,
  19. Keisuke Tateishi1,
  20. Yukimoto Ishii2,
  21. Hiroyuki Isayama7,
  22. Harold L Moses8,
  23. Kazuhiko Koike1
  1. 1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  2. 2Division of Medical Research Planning and Development, Nihon University School of Medicine, Tokyo, Japan
  3. 3Clinical Nutrition Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  4. 4Department of Pathology, Keio University School of Medicine, Tokyo, Japan
  5. 5Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  6. 6Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  7. 7Department of Gastoroenterology, Juntendo University School of Medicine, Tokyo, Japan
  8. 8Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
  1. Correspondence to Dr Hideaki Ijichi, Department of Gastroenterology, The University of Tokyo Graduate School of Medicine Faculty of Medicine, Tokyo 113-8655, Japan; hideijichi-gi{at}umin.ac.jp

Abstract

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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Footnotes

  • MS and RT contributed equally.

  • 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.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to this study are included in the article and supplementary data.If you need to contact us, email address is:hideijichi-gi@umin.ac.jp.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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