COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8070-5. doi: 10.1073/pnas.1424355112. Epub 2015 Jun 15.


The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E2 (PGE2) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE2. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.

Keywords: PGE2; cancer-associated fibroblasts; mPGES-1; neuroblastoma; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosome Deletion
  • Chromosomes, Human, Pair 11
  • Dinoprostone / metabolism*
  • Disease Models, Animal
  • Humans
  • Inflammation / enzymology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism*
  • Mice
  • Neuroblastoma / enzymology
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Prostaglandin-E Synthases
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • RNA, Messenger / genetics
  • Tumor Microenvironment


  • RNA, Messenger
  • Prostaglandin-Endoperoxide Synthases
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone