TY - JOUR
T1 - Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism
AU - Sano, Makoto
AU - Takahashi, Ryota
AU - Ijichi, Hideaki
AU - Ishigaki, Kazunaga
AU - Yamada, Tomoharu
AU - Miyabayashi, Koji
AU - Kimura, Gen
AU - Mizuno, Suguru
AU - Kato, Hiroyuki
AU - Fujiwara, Hiroaki
AU - Nakatsuka, Takuma
AU - Tanaka, Yasuo
AU - Kim, Jinsuk
AU - Masugi, Yohei
AU - Morishita, Yasuyuki
AU - Tanaka, Mariko
AU - Ushiku, Tetsuo
AU - Nakai, Yousuke
AU - Tateishi, Keisuke
AU - Ishii, Yukimoto
AU - Isayama, Hiroyuki
AU - Moses, Harold L.
AU - Koike, Kazuhiko
N1 - Funding Information:
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.
Publisher Copyright:
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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<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.
AB - 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<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.
KW - cell adhesion molecules
KW - pancreatic cancer
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U2 - 10.1136/gutjnl-2020-320608
DO - 10.1136/gutjnl-2020-320608
M3 - Article
C2 - 33087490
AN - SCOPUS:85094215061
VL - 70
SP - 1713
EP - 1723
JO - Gut
JF - Gut
SN - 0017-5749
IS - 9
ER -
