Prostagladin D 2 is a mast cell-derived antiangiogenic factor in lung carcinoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-12, Vol.108 (49), p.19802-19807
• Main Authors: Murata, Takahisa, Aritake, Kosuke, Matsumoto, Shigeko, Kamauchi, Shinya, Nakagawa, Takayuki, Hori, Masatoshi, Momotani, Eiichi, Urade, Yoshihiro, Ozaki, Hiroshi
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1110011108

It is well established that prostaglandins (PGs) are involved in tumor angiogenesis and growth, yet the role of prostaglandin D 2 (PGD 2 ) remains virtually unknown. Here, we show that host hematopoietic PGD 2 synthase (H-PGDS) deficiency enhances Lewis lung carcinoma (LLC) progression, accompanied by increased vascular leakage, angiogenesis, and monocyte/mast cell infiltration. This deficiency can be rescued by hematopoietic reconstitution with bone marrow from H-PGDS–naive (WT) mice. In tumors on WT mice, c-kit + mast cells highly express H-PGDS. Host H-PGDS deficiency markedly up-regulated the expression of proangiogenic factors, including TNF-α in the tumor. In mast cell-null Kit W-sh/W-sh mice, adoptive transfer of H-PGDS–deficient mast cells causes stronger acceleration in tumor angiogenesis and growth than in WT mast cells. In response to LLC growth, H-PGDS–deficient mast cells produce TNF-α excessively. This response is suppressed by the administration of a synthetic PGD 2 receptor agonist or a degradation product of PGD 2 , 15-deoxy-Δ 12,14 -PGJ 2 . Additional TNF-α deficiency partially counteracts the tumorigenic properties seen in H-PGDS–deficient mast cells. These observations identify PGD 2 as a mast cell-derived antiangiogenic factor in expanding solid tumors. Mast cell-derived PGD 2 governs the tumor microenvironment by restricting excessive responses to vascular permeability and TNF-α production.