Singapore Bioimaging Consortium, Agency for Science, Technology and Research, , Singapore, Singapore.
Gut. 2014 Mar;63(3):385-94. doi: 10.1136/gutjnl-2013-305092. Epub 2013 May 31.
To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation.
C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue.
H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6.
Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.
研究肥胖相关炎症和免疫调节在幽门螺杆菌诱导的慢性胃炎症期间对胃癌发生的作用。
将 C57BL/6 雄性小鼠感染 H felis 并置于高脂肪饮食（45％热量来自脂肪）中。分析研究动物的胃和脂肪病理学、血清、胃和脂肪组织中的炎症标志物以及血液、脾脏、胃和脂肪组织中的免疫反应。
与瘦对照组相比，高脂饮食诱导的肥胖小鼠中 H felis 诱导的胃癌发生加速。肥胖增加了 H felis 感染小鼠血液和胃组织中的骨髓来源的未成熟髓样细胞。肥胖还导致 H felis 感染小鼠胃组织中 CD4 T 细胞、IL-17A、粒细胞巨噬细胞集落刺激因子、磷酸化 STAT3 和生存基因表达升高。相反，在肥胖小鼠的脂肪组织中，H felis 感染增加了巨噬细胞的积累和 IL-6、C-C 基序配体 7（CCL7）和瘦素的表达。最后，肥胖和胃炎症的组合协同增加了血清促炎细胞因子，包括 IL-6。
在这里，我们建立了一种模型来研究肥胖使个体易患胃癌的分子机制。在 H felis 感染的小鼠中，肥胖增加了促炎免疫反应并加速了胃癌的发生。有趣的是，胃炎症增强了肥胖诱导的脂肪炎症和肥胖但不是瘦小鼠中脂肪来源因子的产生。我们的研究结果表明，肥胖通过炎症胃和脂肪组织之间细胞因子介导的串扰加速了与幽门螺杆菌相关的胃癌，增强了两个组织部位的免疫反应，从而有助于促进肿瘤发生的胃微环境。
