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Title: Intravital imaging identifies the VEGF-TXA₂ axis as a critical promoter of PGE₂ secretion from tumor cells and immune evasion
Authors: Konishi, Yoshinobu
Ichise, Hiroshi
Watabe, Tetsuya
Oki, Choji
Tsukiji, Shinya
Hamazaki, Yoko
Murakawa, Yasuhiro  kyouindb  KAKEN_id  orcid (unconfirmed)
Takaori-Kondo, Akifumi
Terai, Kenta  kyouindb  KAKEN_id  orcid (unconfirmed)
Matsuda, Michiyuki  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 小西, 義延
一瀬, 大志
渡部, 哲也
沖, 超二
築地, 真也
濱崎, 洋子
村川, 泰裕
高折, 晃史
寺井, 健太
松田, 道行
Issue Date: Aug-2021
Publisher: American Association for Cancer Research (AACR)
Journal title: Cancer Research
Volume: 81
Issue: 15
Start page: 4124
End page: 4132
Abstract: Prostaglandin E₂ (PGE₂) promotes tumor progression through evasion of anti-tumor immunity. In stark contrast to cyclooxygenase-dependent production of PGE₂, little is known whether or not PGE₂ secretion is regulated within tumor tissues. Here, we show that VEGF-dependent release of thromboxane A₂ (TXA₂) triggers Ca²⁺ transients in tumor cells, culminating in PGE₂ secretion and subsequent immune evasion in the early stages of tumorigenesis. Ca²⁺ transients caused cPLA2 activation and triggered the arachidonic acid cascade. Ca²⁺ transients were monitored as the surrogate marker of PGE₂ secretion. Intravital imaging of BrafV600E mouse melanoma cells revealed that the proportion of cells exhibiting Ca²⁺ transients is markedly higher in vivo than in vitro. The TXA₂ receptor was indispensable for the Ca²⁺ transients in vivo, high intra-tumoral PGE₂ concentration, and evasion of anti-tumor immunity. Notably, treatment with a vascular endothelial growth factor (VEGF) receptor antagonist and an anti-VEGF antibody rapidly suppressed Ca²⁺ transients and reduced TXA₂ and PGE₂ concentrations in tumor tissues. These results identify the VEGF-TXA₂ axis as a critical promoter of PGE₂-dependent tumor immune evasion, providing a molecular basis underlying the immunomodulatory effect of anti-VEGF therapies.
Description: がん細胞が免疫から逃れるメカニズムの解明 --がん細胞と血管内皮細胞との細胞間相互作用--. 京都大学プレスリリース. 2021-05-28.
Rights: The full-text file will be made open to the public on 25 May 2022 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1158/0008-5472.CAN-20-4245
PubMed ID: 34035084
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