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: 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 EP4A.Tumors revealed high incidence of EP4-expressing, VEGF-C/D producing macrophages identified with dual immunostaining of F4/80 and EP4 or VEGF-C/D.Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs.
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.