Soluble factors for thrombosis associated with pancreatic cancer

• Project/Area Number: 19K16533
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ishigaki Kazunaga 東京大学, 医学部附属病院, 特任講師 (60836287)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵がん / 膵癌 / exosome / 血栓 / 液性因子

Outline of Research at the Start

血栓塞栓症は担癌患者でよくみられる合併症であるが、膵癌は癌の中でも血栓塞栓症の頻度の高い癌である。本研究では、膵癌による血栓塞栓症発症の病態生理の解明のために、自身の臨床的な知見を背景にして、膵癌細胞が分泌するexosomeなどの液性因子が血管内皮細胞の凝固線溶因子の発現に何らかの影響を及ぼしているのではないかとの仮説をたててそれを検証する。膵癌細胞株の上清からのexosome、あるいは膵癌自然発症遺伝子改変マウスの血清中のexosomeを用いて、血管内皮細胞での凝固線溶因子の発現・活性化の変化を検討し、その責任分子を分子生物学的に同定することで発症機序の解明をめざす。

Outline of Final Research Achievements

Thromboembolism is a common complication in cancer-bearing patients, and is the second leading cause of death in cancer patients. Among cancers, pancreatic cancer is prone to develop thromboembolism, and in this study, we investigated the pathogenic mechanism of thromboembolism, which is closely related to the prognosis of pancreatic cancer patients. Since it seemed that liver metastasis is the largest risk factor for the development of thromboembolism, some humoral factor secreted by pancreatic cancer cells were likely to cause systemic thromboembolism. As a result of the examination, it was suggested that the development of pancreatic cancer tissue is influenced by VEGF, and that a large amount of extracellular vesicles released from cancer tissues induces thromboembolisms at the vascular endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

本研究は 膵がんで合併することの多い血栓塞栓症の機序を解明するべく、膵癌組織から何かしらの液性因子が放出されることで血栓素因が形成されるのではないかという仮説のもとに検討を行った。種々の分子生物学的手法を用いて、最終的に可溶性のVCAM1という因子が膵癌組織から放出されそれが血栓形成に関与している可能性をみいだした。この結果から、例えば抗体などを用いてそのメカニズムに介入することで、上記のような膵癌に伴う血栓形成による病態の悪化を防ぐことが可能となるかもしれない。そうなれば予後の悪い膵癌の予後延長に寄与できる可能性がある。

Research Products

• [Journal Article] MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages (2022)
  • Author(s): Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, et al.
  • Journal Title: Gastroenterology Volume: 162 Issue: 4 Pages: 1272-1287
  • DOI: 10.1053/j.gastro.2021.12.254
  • Peer Reviewed / Open Access
• [Journal Article] Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism (2020)
  • Author(s): Sano M, Takahashi R, Ijichi H, Ishigaki K, Yamada T, Miyabayashi K, Kimura G, Mizuno S, Kato H, Fujiwara H, Nakatsuka T, Tanaka Y, Kim J, Masugi Y, Morishita Y, Tanaka M, Uikshiku T, Nakai Y, Tateishi K, Ishii Y, Isayama H, Moses HL, Koike K
  • Journal Title: Gut Volume: 70 Issue: 9 Pages: 1713-1723
  • DOI: 10.1136/gutjnl-2020-320608
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endoscopic Ultrasound-Guided Tissue Acquisition by 22-Gauge Franseen and Standard Needles for Solid Pancreatic Lesions (2020)
  • Author(s): Ishigaki Kazunaga、Nakai Yousuke、Oyama Hiroki、Kanai Sachiko、Suzuki Tatsunori、Nakamura Tomoka、Sato Tatsuya、Hakuta Ryunosuke、Saito Kei、Saito Tomotaka、Takahara Naminatsu、Hamada Tsuyoshi、Mizuno Suguru、Kogure Hirofumi、Tada Minoru、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Gut and Liver Volume: 14 Issue: 6 Pages: 817-825
  • DOI: 10.5009/gnl19171
  • Peer Reviewed / Open Access
• [Journal Article] Regular Statin Use and Incidence of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis (2019)
  • Author(s): Hakuta Ryunosuke、Nakai Yousuke、Hamada Tsuyoshi、Suzuki Yukari、Inokuma Akiyuki、Oyama Hiroki、Kanai Sachiko、Nakamura Tomoka、Sato Tatsuya、Ishigaki Kazunaga、Saito Kei、Saito Tomotaka、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Tada Minoru、Koike Kazuhiko
  • Journal Title: Journal of Clinical Gastroenterology Volume: ー Issue: 10 Pages: 1-1
  • DOI: 10.1097/mcg.0000000000001312
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic yield of the plasma free amino acid index for pancreatic cancer in patients with diabetes mellitus (2019)
  • Author(s): Mizuno Suguru、Isayama Hiroyuki、Nakai Yousuke、Ishigaki Kazunaga、Saito Kei、Sato Tatsuya、Takeda Tsuyoshi、Hakuta Ryunosuke、Saito Tomotaka、Takahara Naminatsu、Kogure Hirofumi、Ijichi Hideaki、Tateishi Keisuke、Tada Minoru、Shikata Nahoko、Tagami Tomoyuki、Koike Kazuhiko
  • Journal Title: Pancreatology Volume: 19 Issue: 5 Pages: 695-698
  • DOI: 10.1016/j.pan.2019.07.002
  • Peer Reviewed / Open Access