Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions.
Bottom Line: Treating murine macrophage RAW 264.7 cell line with COX-2i celecoxib and EP4A significantly reduced VEGF-A/C/D production in vitro, measured with quantitative PCR and Western blots.Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs.Knocking down COX-2 or EP4 in C3L5 cells or treating cells in vitro with celecoxib or EP4A 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 ALDH1A, CD44, OCT-3/4, β-catenin, and SOX-2.
Affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.Show MeSH
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Mentions: Implants of Matrigel alone appeared as clear avascular jelly beans (Fig.1a, shown for day 16) at all time points with no evidence of angiogenesis or lymphangiogenesis, as previously reported.10,38 Tumor growth was significantly blocked (at all time points) with both EP4A (as early as day 8) and celecoxib treatments (Fig.1b). Spontaneous lung metastases are shown in Figure1(c), as surface colonies and microscopic colonies (Fig.1d) on day 12. The incidence of microscopic colonies was high in vehicle-treated mice on day 8, with a further small increase on days 12 and 16. There was a significant reduction of lung colonies at all time points with celecoxib and EP4A treatments (Fig.1e).
Affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.