Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response
Objective: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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BMJ Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/88720 https://orcid.org/0000-0001-9307-6116 |
| _version_ | 1826206057823731712 |
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| author | Ericksen, Russell E. Rose, Shannon Westphalen, Christoph Benedikt Shibata, Wataru Muthupalani, Sureshkumar Tailor, Yagnesh Friedman, Richard A. Han, Weiping Fox, James G. Ferrante, Anthony W. Wang, Timothy C. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Ericksen, Russell E. Rose, Shannon Westphalen, Christoph Benedikt Shibata, Wataru Muthupalani, Sureshkumar Tailor, Yagnesh Friedman, Richard A. Han, Weiping Fox, James G. Ferrante, Anthony W. Wang, Timothy C. |
| author_sort | Ericksen, Russell E. |
| collection | MIT |
| description | Objective: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation.
Design: 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.
Results: 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.
Conclusions: 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. |
| first_indexed | 2024-09-23T13:23:25Z |
| format | Article |
| id | mit-1721.1/88720 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:23:25Z |
| publishDate | 2014 |
| publisher | BMJ Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/887202022-10-01T14:56:27Z Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response Ericksen, Russell E. Rose, Shannon Westphalen, Christoph Benedikt Shibata, Wataru Muthupalani, Sureshkumar Tailor, Yagnesh Friedman, Richard A. Han, Weiping Fox, James G. Ferrante, Anthony W. Wang, Timothy C. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Division of Comparative Medicine Muthupalani, Sureshkumar Fox, James G. Objective: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design: 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. Results: 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. Conclusions: 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. National Institutes of Health (U.S.) (grant 5R01CA093405-11) Columbia University Medical Center (Naomi Berrie Diabetes Center, grant P30DK063608) 2014-08-15T16:25:43Z 2014-08-15T16:25:43Z 2013-05 2013-05 Article http://purl.org/eprint/type/JournalArticle 0017-5749 1468-3288 http://hdl.handle.net/1721.1/88720 Ericksen, R. E., S. Rose, C. B. Westphalen, W. Shibata, S. Muthupalani, Y. Tailor, R. A. Friedman, et al. “Obesity Accelerates Helicobacter Felis-Induced Gastric Carcinogenesis by Enhancing Immature Myeloid Cell Trafficking and TH17 Response.” Gut 63, no. 3 (May 31, 2013): 385–394. doi:10.1136/gutjnl-2013-305092. https://orcid.org/0000-0001-9307-6116 en_US http://dx.doi.org/10.1136/gutjnl-2013-305092 Gut Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf BMJ Publishing Group PMC |
| spellingShingle | Ericksen, Russell E. Rose, Shannon Westphalen, Christoph Benedikt Shibata, Wataru Muthupalani, Sureshkumar Tailor, Yagnesh Friedman, Richard A. Han, Weiping Fox, James G. Ferrante, Anthony W. Wang, Timothy C. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response |
| title | Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response |
| title_full | Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response |
| title_fullStr | Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response |
| title_full_unstemmed | Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response |
| title_short | Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response |
| title_sort | obesity accelerates helicobacter felis induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and th17 response |
| url | http://hdl.handle.net/1721.1/88720 https://orcid.org/0000-0001-9307-6116 |
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