Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer
Contribuinte(s) |
Health Research Board Irish Cancer Society Science Foundation Ireland |
---|---|
Data(s) |
31/07/2013
31/07/2013
01/08/2013
03/07/2013
|
Resumo |
Despite studies demonstrating that inhibition of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has significant chemotherapeutic benefits in vitro and in vivo, inhibition of COX enzymes is associated with serious gastrointestinal and cardiovascular side effects, limiting the clinical utility of these drugs. PGE2 signals through four different receptors (EP1–EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. Here, we show that targeted inhibition of the EP1 receptor in the tumor cells and the tumor microenvironment resulted in the significant inhibition of tumor growth in vivo. Both dietary administration and direct injection of the EP1 receptor-specific antagonist, ONO-8713, effectively reduced the growth of established CT26 tumors in BALB/c mice, with suppression of the EP1 receptor in the tumor cells alone less effective in reducing tumor growth. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4+CD25+Foxp3+ regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased. F4/80+ macrophage infiltration was also decreased; however, there was no change in macrophage phenotype. These findings suggest that the EP1 receptor represents a potential target for the treatment of colon cancer. Health Research Board of Ireland (RP/2007/8); Irish Cancer Society (CRF12RYA) Submitted Version Peer reviewed |
Formato |
application/pdf |
Identificador |
O'Callaghan G, Ryan A, Neary P, O'Mahony C, Shanahan F, Houston A (2013) 'Targeting the EP1 receptor reduces fas ligand expression and increases the anti-tumor immune response in an in vivo model of colon cancer'. International Journal of Cancer, 133 (4):825-834. doi: 10.1002/ijc.28076 133 4 825 834 1097-0215 0020-7136 http://hdl.handle.net/10468/1206 10.1002/ijc.28076 International Journal of Cancer |
Idioma(s) |
en |
Publicador |
Wiley |
Direitos |
Copyright © 2013 UICC. The definitive version is available at www3.interscience.wiley.com |
Palavras-Chave | #PGE2 #EP1 receptor #Immune suppression #Cancer |
Tipo |
Article (peer-reviewed) |