Prostaglandin E₂ signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors

Gastroenterology. 2011 Feb;140(2):596-607.e7. doi: 10.1053/j.gastro.2010.11.007. Epub 2010 Nov 9.


Background & aims: Helicobacter pylori infection induces an inflammatory response, which can contribute to gastric tumorigenesis. Induction of cyclooxygenase-2 (COX-2) results in production of prostaglandin E(2) (PGE(2)), which mediates inflammation. We investigated the roles of bacterial infection and PGE(2) signaling in gastric tumorigenesis in mice.

Methods: We generated a germfree (GF) colony of K19-Wnt1/C2mE mice (Gan mice); these mice develop gastric cancer. We examined tumor phenotypes, expression of cytokines and chemokines, and recruitment of macrophages. We also investigated PGE(2) signaling through the PGE(2) receptor subtype 4 (EP4) in Gan mice given specific inhibitors.

Results: Gan mice raised in a specific pathogen-free facility developed large gastric tumors, whereas gastric tumorigenesis was significantly suppressed in GF-Gan mice; reconstitution of commensal flora or infection with Helicobacter felis induced gastric tumor development in these mice. Macrophage infiltration was significantly suppressed in the stomachs of GF-Gan mice. Gan mice given an EP4 inhibitor had decreased expression of cytokines and chemokines. PGE(2) signaling and bacterial infection or stimulation with lipopolysaccharide induced expression of the chemokine C-C motif ligand 2 (CCL2) (which attracts macrophage) in tumor stromal cells or cultured macrophages, respectively. CCL2 inhibition suppressed macrophage infiltration in tumors, and depletion of macrophages from the tumors of Gan mice led to signs of tumor regression. Wnt signaling was suppressed in the tumors of GF-Gan and Gan mice given injections of tumor necrosis factor-α neutralizing antibody.

Conclusions: Bacterial infection and PGE(2) signaling are required for gastric tumorigenesis in mice; they cooperate to up-regulate CCL2, which recruits macrophage to gastric tumors. Macrophage-derived tumor necrosis factor-α promotes Wnt signaling in epithelial cells, which contributes to gastric tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Benzamides / pharmacology
  • Celecoxib
  • Cell Line
  • Cell Transformation, Neoplastic*
  • Chemokine CCL2 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Cytokines / metabolism
  • Dinoprostone / physiology*
  • Female
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / microbiology
  • Germ-Free Life
  • Helicobacter Infections / complications*
  • Helicobacter Infections / metabolism
  • Helicobacter felis
  • Macrophages / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pyrazoles / pharmacology
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Stomach Neoplasms / microbiology*
  • Stomach Neoplasms / pathology
  • Sulfonamides / pharmacology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Wnt Proteins / metabolism
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism


  • (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid
  • Antibodies, Neutralizing
  • Benzamides
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Cyclooxygenase 2 Inhibitors
  • Cytokines
  • Pyrazoles
  • Receptors, Prostaglandin E, EP4 Subtype
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone