Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
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.
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.
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.
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.
幽门螺杆菌感染会引起炎症反应，从而促进胃肿瘤的发生。环氧化酶-2（COX-2）的诱导会导致前列腺素 E2（PGE2）的产生，从而介导炎症反应。我们研究了细菌感染和 PGE2 信号在小鼠胃肿瘤发生中的作用。
我们生成了 K19-Wnt1/C2mE 小鼠（Gan 小鼠）的无菌（GF）品系；这些小鼠会发展为胃癌。我们检查了肿瘤表型、细胞因子和趋化因子的表达以及巨噬细胞的募集情况。我们还通过给予 Gan 小鼠特异性抑制剂来研究 PGE2 信号通过 PGE2 受体亚型 4（EP4）的作用。
在特定病原体无设施中饲养的 Gan 小鼠会发展出大型胃肿瘤，而 GF-Gan 小鼠中的胃肿瘤发生则受到显著抑制；共生菌群的重建或感染 Helicobacter felis 会诱导这些小鼠发生胃肿瘤。GF-Gan 小鼠胃中的巨噬细胞浸润明显受到抑制。给予 Gan 小鼠 EP4 抑制剂会导致细胞因子和趋化因子的表达减少。PGE2 信号和细菌感染或脂多糖刺激分别诱导肿瘤基质细胞或培养的巨噬细胞中趋化因子 C-C 基序配体 2（CCL2）（吸引巨噬细胞）的表达。CCL2 抑制会抑制肿瘤中的巨噬细胞浸润，并且从 Gan 小鼠肿瘤中耗尽巨噬细胞会导致肿瘤消退的迹象。GF-Gan 小鼠肿瘤和给予肿瘤坏死因子-α中和抗体注射的 Gan 小鼠中的 Wnt 信号受到抑制。
细菌感染和 PGE2 信号对于小鼠胃肿瘤发生是必需的；它们共同上调 CCL2，从而招募巨噬细胞到胃肿瘤中。巨噬细胞衍生的肿瘤坏死因子-α促进上皮细胞中的 Wnt 信号，从而促进胃肿瘤的发生。
