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We previously established that  COX ‐2 overexpression promotes breast cancer progression and metastasis. As long‐term use of  COX ‐2 inhibitors ( COX ‐2i) can promote thrombo‐embolic events, we tested an alternative target, prostaglandin E2 receptor  EP 4 subtype ( EP 4), downstream of  COX ‐2. Here we used the highly metastatic syngeneic murine C3L5 breast cancer model to test the role of  EP 4‐expressing macrophages in vascular endothelial growth factor ( VEGF )‐C/D production, angiogenesis, and lymphangiogenesis  in situ , the role of  EP 4 in stem‐like cell ( SLC ) functions of tumor cells, and therapeutic effects of an  EP 4 antagonist  RQ ‐15986 ( EP 4A). C3L5 cells expressed all  EP  receptors, produced  VEGF ‐C/D, and showed high clonogenic tumorsphere forming ability  in vitro , functions inhibited with  COX ‐2i or  EP 4A. Treating murine macrophage  RAW  264.7 cell line with  COX ‐2i celecoxib and  EP 4A significantly reduced  VEGF ‐A/C/D production  in vitro , measured with quantitative  PCR  and Western blots. Orthotopic implants of C3L5 cells in C3H/HeJ mice showed rapid tumor growth, angiogenesis, lymphangiogenesis ( CD 31/ LYVE ‐1 and  CD 31/ PROX 1 immunostaining), and metastasis to lymph nodes and lungs. Tumors revealed high incidence of  EP 4‐expressing,  VEGF ‐C/D producing macrophages identified with dual immunostaining of F4/80 and  EP 4 or  VEGF ‐C/D. Celecoxib or  EP 4A therapy at non‐toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in treated mice revealed markedly reduced  VEGF ‐A/C/D and phosphorylated Akt/ ERK  proteins,  VEGF ‐C/D positive macrophage infiltration, and proliferative/apoptotic cell ratios. Knocking down   COX ‐2  or   EP 4  in C3L5 cells or treating cells  in vitro  with celecoxib or  EP 4A and treating tumor‐bearing mice  in vivo  with the same drug reduced  SLC  properties of tumor cells including preferential co‐expression of  COX ‐2 and  SLC  markers  ALDH 1A,  CD 44,  OCT ‐3/4, β‐catenin, and  SOX ‐2. Thus,  EP 4 is an excellent therapeutic target to block stem‐like properties, angiogenesis, and lymphangiogenesis induced by  VEGF ‐A/C/D secreted by cancer cells and tumor infiltrating macrophages.

cancer science

Prostaglandin E2 receptor  EP 4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem‐like cell functions