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Angiogenesis: Prostaglandin D2 signals bad news for tumours

Lipidomics Gateway (28 December 2011) [doi:10.1038/lipidmaps.2011.36]

Prostaglandin D2 derived from tumour-infiltrating mast cells confers anti-angiogenic properties by suppressing the production of TNF and vascular leakage.

Macmillan Image Bank

Taking common non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase-dependent synthesis of prostaglandins (PGs), can reportedly stave off cancer, with PGE2, for example, being implicated in tumour angiogenesis and growth. PGD2, however, can function as a pro- or anti-inflammatory mediator, depending on the target cell, and Murata et al. now report that, in the context of lung tumours, PGD2 derived from infiltrating mast cells has anti-angiogenic properties.

Infiltrating inflammatory cells are generally thought to supply growth factors and cytokines that promote tumour angiogenesis and growth, but mice lacking haematopoietic PGD2 synthase (H-PGDS−/− mice) supported the accelerated growth of implanted Lewis lung carcinoma (LLC) or B16 melanoma tumours when compared to wild-type mice. Tumours implanted into H-PGDS-deficient mice displayed enhanced angiogenesis, a less mature and more leaky vasculature, and fewer apoptotic cells than those implanted into wild-type animals; however, haematopoietic reconstitution of H-PGDS−/− mice with bone marrow from wild-type mice increased tumour-cell apoptosis, indicating that PGD2 derived from haematopoietic lineage cells usually limits tumour-cell survival, presumably by reducing vascular leakage and angiogenesis.

Murata et al. then showed that tumour pieces from H-PGDS−/− mice, when transplanted into mouse corneas, enhanced the angiogenic response and expressed higher levels of pro-angiogenic genes, such as those encoding tumour necrosis factor (TNF), compared with those from wild-type mice. They also showed that host H-PGDS deficiency increased the production of TNF in implanted tumours, but that haematopoietic reconstitution suppressed this increase. Immunostaining revealed that infiltrating mast cells provided the source of both H-PGDS and TNF in tumours implanted into wild-type animals; interestingly, host-cell H-PGDS-deficiency accelerated mast-cell infiltration into the tumours.

Having demonstrated in vitro that bone marrow-derived mast cells lacking H-PGDS secreted increased amounts of TNF compared with wild-type cells in response to antigenic stimulation, Murata et al. then observed increased tumorigenesis in mice lacking mature mast cells into which bone marrow-derived mast cells lacking H-PGDS were transferred; this increase was reduced when the gene encoding TNF was additionally disrupted. These data indicate that mast-cell-derived PGD2 and TNF have an essential role in tumour expansion, by enhancing endothelial cell number and vascular permeability, increasing fibrinogen deposition and enhancing monocyte/macrophage infiltration, and that TNF somehow enhances the tumorigenic properties of H-PGDS−/− mast cells. Further analysis revealed that PGD2 usually suppresses the production of TNF in mast cells to confer anti-angiogenic properties.

Finally, consistent with PGD2 inhibiting the production of TNF in mast cells, Murata et al. observed that mast cells from H-PGDS−/− mice infiltrated the peritoneal cavity and overexpressed TNF in response to peritoneal inoculation of LLC cells, and that this increase in expression, alongside increased infiltration, could be blocked by the administration of a synthetic agonist of the D prostanoid receptor, a degradation product of PGD2 (15-deoxy-Δ12,14-PGJ2), or a synthetic activator of peroxisome proliferator-activated receptor-γ that is reported to be downstream target of 15-deoxy-Δ12,14-PGJ2.

This study has identified that, contrary to the widely-held belief that prostaglandins promote tumorigenesis, PGD2 manifests anti-angiogenic properties when derived from tumour-infiltrating mast cells, by inhibiting autonomous TNF production and vascular hyperpermeability. Given the widespread distribution of mast cells and their involvement in other pathophysiological conditions such as allergy and cardiovascular disease, inhibiting their activity — by enhancing the production of PGD2 — might therefore prove a useful therapeutic strategy.

Katrin Legg

- Copyright © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission



  1. Murata, T. et al. Prostaglandin D2 is a mast cell-derived antiangiogenic factor in lung carcinoma.

    Proc. Natl Acad. Sci. USA (21 November 2012). doi:10.1073/pnas.1110011108

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