| RRC ID |
65076
|
| 著者 |
Konishi Y, Ichise H, Watabe T, Oki C, Tsukiji S, Hamazaki Y, Murakawa Y, Takaori-Kondo A, Terai K, Matsuda M.
|
| タイトル |
Intravital Imaging Identifies the VEGF-TXA2 Axis as a Critical Promoter of PGE2 Secretion from Tumor Cells and Immune Evasion.
|
| ジャーナル |
Cancer Res
|
| 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.
|
| 巻・号 |
81(15)
|
| ページ |
4124-4132
|
| 公開日 |
2021-8-1
|
| DOI |
10.1158/0008-5472.CAN-20-4245
|
| PII |
0008-5472.CAN-20-4245
|
| PMID |
34035084
|
| MeSH |
Animals
Dinoprostone / immunology*
Humans
Immune Evasion / immunology*
Intravital Microscopy / methods*
Mice
Mice, Nude
Vascular Endothelial Growth Factor A / immunology*
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
MDCK(RCB0995) |
