Cancer and Prostaglandin E2: Don't make it, or break it?

Lipidomics Gateway (24 June 2009) [doi:10.1038/lipidmaps.2009.14]

A lack of prostaglandin dehydrogenase prevents catabolism of prostaglandin E2, helping cancer cells both to evade the immune system and circumvent drug treatment.

Prostaglandin E2 (PGE2, see Lipid of the month) is overproduced in many tumors, where it aids cancer progression by promoting angiogenesis and metastasis, and by influencing the immune response. Inhibitors of the PGE2 biosynthetic enzyme cyclooxygenase 2 (COX-2) are used to treat pain and inflammation and are showing promise as cancer treatments. However, inhibiting COX-2 can produce serious side effects, and some individuals exhibit resistance to tumor prevention by the COX-2 inhibitor celecoxib. Focusing on the degradation of PGE2 by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is an alternative route to reducing PGE2 levels in tumors. Two new studies highlight the potential of this approach: reporting in the Journal of Immunology, Eruslanov et al. demonstrate the role of 15-PGDH in the regulation of the local antitumor immune response; and a paper in Proceedings of the National Academy of Sciences of the USA by Yan et al. shows that low levels of 15-PGDH are responsible for the failure of celecoxib to prevent recurrence of colon adenomas in some patients.

Structure of 15-hydroxyprostaglandin dehydrogenase with PGE2 and NAD+ docked. Full figure: Nature Genetics 40, 789—793 (2008) doi:10.1038/ng.153

Inappropriately dividing cells activate immune responses, which begin with inflammation mediated by macrophages and their precursors, monocytes. Secreted cytokines then stimulate dendritic cells to mature and present antigens to T lymphocytes, initiating destruction of the nascent tumor. Tumor cells can escape destruction by producing signals to interfere with antigen presentation or maturation of dendritic cells, with precursors maturing into immunosuppressive cell types instead. Once subverted in this way, inflammation can assist tumor growth by, for example, promoting angiogenesis._However, regulation of the inflammatory tumor microenvironment is poorly understood.

Eruslanov et al. examined 15-PGDH expression and PGE2 levels in intra-tumoral immune cells, specifically non-lymphocyte white blood cells expressing the marker CD11b. Freshly isolated from mouse tumors, CD11b cells had markedly increased PGE2 levels, higher COX-2 expression and significantly reduced expression of 15-PGDH than cells from outside the tumor. Injection of an adenovirus encoding 15-PGDH into mouse tumors significantly slowed tumor growth. The resultant 15-PGDH expression was highest in tumor cells but also significant in tumor-associated CD11b cells, where it produced a fourfold reduction in PGE2 secretion. This was associated with reduced secretion of immunosuppressive cytokines by the CD11b cells and it resulted in a switch in their fate, promoting their differentiation into dendritic cells. Overproduction of PGE2 in tumors therefore contributes to immune evasion by preventing maturation of antigen-presenting cells, and this can be overcome by enforced expression of 15-PGDH.

The potential therapeutic benefit of focusing on PGE2 catabolism is emphasized in the study by Yan et al. Celecoxib, a non-steroidal anti-inflammatory COX-2 inhibitor used to treat pain and inflammation, reduces the recurrence of colon adenomas but does not work in some patients. The authors found that in mice, gene knockout of 15-PGDH confers near-complete resistance to the ability of celecoxib to prevent colon tumors. Furthermore, the 15-PGDH levels of people from a trial of celecoxib for adenoma prevention were lowest in those for whom the treatment failed.

These studies highlight the potential importance of reducing PGE2 levels in cancer, and indicate that focusing on its catabolism could augment or replace the effect of preventing its production.

Emma Leah