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

金沢大学がん研究所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 E2 (PGE2), which mediates inflammation. We investigated the roles of bacterial infection and PGE2 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 PGE2 signaling through the PGE2 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. PGE2 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 PGE2 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. © 2011 AGA Institute

PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice

A new mouse model of spontaneous autoimmune disease reveals an important role for the inhibitory co-receptor LAG-3 in suppressing autoimmunity

Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of the Notch1 Gene in Mouse Thymic Lymphomas

Deregulated V(D)J recombination-mediated chromosomal rearrangements are implicated in the etiology of B- and T-cell lymphomagenesis. We describe here three pathways for the formation of the 5\u27 deletions of Notch1 gene in thymic lymphomas of wild-type or V(D)J recombination-defective scid mice. A pair of recombination signal sequence -like sequences composed of heptamer-like and nonamer-like motifs separated by 12- or 23-bp spacers (12- or 23-recombination signal sequence) were present in the vicinity of the deletion breakpoints in wild-type thymic lymphomas, accompanied by palindromic or nontemplated nucleotides at the junctions. In scid thymic lymphomas the deletions at the recombination signal sequence-like sequences occurred at a significantly lower frequency than in wild-type mice, whereas the deletions did not occur in Rag2-/- thymocytes. These results show that the 5\u27 deletions are formed by Rag-mediated V(D)J recombination machinery at cryptic recombination signal sequences in the Notch1 locus. In contrast, one third of the deletions in radiation-induced scid thymic lymphomas had microhomology at both ends, indicating that in the absence of DNA-dependent protein kinase-dependent nonhomologous end-joining, the microhomology-mediated nonhomologous endjoining pathway functions as a main mechanism to produce deletions. Furthermore the deletions were induced via a coupled pathway between Rag-mediated cleavage at cryptic recombination signal sequence and micronomology-mediated end-joining in radiation-induced scid thymic lymphomas. As the deletions at cryptic recombination signal sequence occur spontaneously, microhomology-mediated pathways might participate mainly in in radiation-induced lymphomagenesis. Recombination signal sequence-mediated deletions were present clonally in thymocyte population, suggesting that thymocytes with a 5\u27deletion of the Notch1 gene have a growth advantage and are involved in lymphomagenesis