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Detail of Figure5AB_Ptgs2KO_N3

Yoshinobu Konishi, Hiroshi Ichise, Tetsuya Watabe, Choji Oki, Shinya Tsukiji, Yoko Hamazaki, Yasuhiro Murakawa, Akifumi Takaori-Kondo, Kenta Terai, Michiyuki Matsuda (2021) Intravital Imaging Identifies the VEGF-TXA2 Axis as a Critical Promoter of PGE2 Secretion from Tumor Cells and Immune Evasion., Cancer research, Volume 81, Number 15, pp. 4124-4132

Published in 2021 Aug 1 (Electronic publication in May 25, 2021, midnight )

• doi: 10.1158/0008-5472.CAN-20-4245
• pmid: 34035084
  

(Abstract) Prostaglandin E2 (PGE2) promotes tumor progression through evasion of antitumor immunity. In stark contrast to cyclooxygenase-dependent production of PGE2, little is known whether PGE2 secretion is regulated within tumor tissues. Here, we show that VEGF-dependent release of thromboxane A2 (TXA2) triggers Ca(2+) transients in tumor cells, culminating in PGE2 secretion and subsequent immune evasion in the early stages of tumorigenesis. Ca(2+) transients caused cPLA2 activation and triggered the arachidonic acid cascade. Ca(2+) transients were monitored as the surrogate marker of PGE2 secretion. Intravital imaging of Braf(V600E) mouse melanoma cells revealed that the proportion of cells exhibiting Ca(2+) transients is markedly higher in vivo than in vitro. The TXA2 receptor was indispensable for the Ca(2+) transients in vivo, high intratumoral PGE2 concentration, and evasion of antitumor immunity. Notably, treatment with a VEGF receptor antagonist and an anti-VEGF antibody rapidly suppressed Ca(2+) 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. SIGNIFICANCE: This study identifies the VEGF-TXA2 axis as a potentially targetable regulator of PGE2 secretion, which provides novel strategies for prevention and treatment of multiple types of malignancies.

• Animals
• Dinoprostone/immunology[major]
• Humans
• Immune Evasion/immunology[major]
• Intravital Microscopy/methods[major]
• Mice
• Mice, Nude
• Vascular Endothelial Growth Factor A/immunology[major]