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 PGD₂ remains virtually unknown. Here we show that PGD₂ receptor (DP) deficiency enhances tumor progression accompanied by abnormal vascular expansion. In tumors, angiog...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008, Vol.105 (50), p.20009-20014
Main Authors: Murata, Takahisa, Lin, Michelle I, Aritake, Kosuke, Matsumoto, Shigeko, Narumiya, Shu, Ozaki, Hiroshi, Urade, Yoshihiro, Hori, Masatoshi, Sessa, William C
Format: Article
Language:English
Subjects:
agonists
angiogenesis
cornea
cyclic AMP
endothelial cells
in vitro studies
mice
neoplasms
permeability
prostaglandins
therapeutics
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Summary:Although COX-dependent production of prostaglandins (PGs) is known to be crucial for tumor angiogenesis and growth, the role of PGD₂ remains virtually unknown. Here we show that PGD₂ 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 PGD₂/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.
ISSN:0027-8424
1091-6490