Prostagladin D2 is a mast cell-derived antiangiogenic factor in lung carcinoma
Menée à l'aide d'un modèle murin de cancer pulmonaire, cette étude identifie un mécanisme par lequel la prostaglandine D2, exprimée dans les mastocytes du micro-environnement tumoral, régule l'angiogenèse
It is well established that prostaglandins (PGs) are involved in tumor angiogenesis and growth, yet the role of prostaglandin D2 (PGD2) remains virtually unknown. Here, we show that host hematopoietic PGD2 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 KitW-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 PGD2 receptor agonist or a degradation product of PGD2, 15-deoxy-Δ12,14-PGJ2. Additional TNF-α deficiency partially counteracts the tumorigenic properties seen in H-PGDS–deficient mast cells. These observations identify PGD2 as a mast cell-derived antiangiogenic factor in expanding solid tumors. Mast cell-derived PGD2 governs the tumor microenvironment by restricting excessive responses to vascular permeability and TNF-α production.