Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo.
Although COX-dependent production of prostaglandins (PGs) is known to be crucial for tumor angiogenesis and growth, the role of PGD(2) remains virtually unknown. Here we show that PGD(2) receptor (DP) deficiency enhances tumor progression accompanied by abnormal vascular expansion. In tumors, angiogenic endothelial cells highly express DP receptor, and its deficiency accelerates vascular leakage and angiogenesis. Administration of a synthetic DP agonist, BW245C, markedly suppresses tumor growth as well as tumor hyperpermeability in WT mice, but not in DP-deficient mice. In a corneal angiogenesis assay and a modified Miles assay, host DP deficiency potentiates angiogenesis and vascular hyperpermeability under COX-2-active situation, whereas exogenous administration of BW245C strongly inhibits both angiogenic properties in WT mice. In an in vitro assay, BW245C does not affect endothelial migration and tube formation, processes that are necessary for angiogenesis; however, it strongly improves endothelial barrier function via an increase in intracellular cAMP production. Our results identify PGD(2)/DP receptor as a new regulator of tumor vascular permeability, indicating DP agonism may be exploited as a potential therapy for the treatment of cancer.
Murata
Takahisa
T
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 133-8657, Japan.
Lin
Michelle I
MI
Aritake
Kosuke
K
Matsumoto
Shigeko
S
Narumiya
Shu
S
Ozaki
Hiroshi
H
Urade
Yoshihiro
Y
Hori
Masatoshi
M
Sessa
William C
WC
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation; D016510:Corneal Neovascularization / Q000139:chemically induced; D000242:Cyclic AMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006827:Hydantoins / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D006827:Hydantoins; D053583:Interleukin-1beta; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D042461:Vascular Endothelial Growth Factor A; C030669:BW 245C; D000242:Cyclic AMP; C036293:prostaglandin D2 receptor