%0 Journal Article %1 Doerner:2016dta %A Doerner, Stephanie K %A Reis, Edimara S %A Leung, Elaine S %A Ko, Justine S %A Heaney, Jason D %A Berger, Nathan A %A Lambris, John D. %A Nadeau, Joseph H %D 2016 %J Molecular cancer research : MCR %K imported %N 10 %P 953--965 %R 10.1158/1541-7786.MCR-16-0153 %T High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity. %U http://mcr.aacrjournals.org/cgi/doi/10.1158/1541-7786.MCR-16-0153 %V 14 %X Obesity and related metabolic disturbances are closely associated with pathologies that represent a significant burden to global health. Epidemiological and molecular evidence links obesity and metabolic status with inflammation and increased risk of cancer. Here, using a mouse model of intestinal neoplasia and strains that are susceptible or resistant to diet-induced obesity, it is demonstrated that high-fat diet-induced inflammation, rather than obesity or metabolic status, is associated with increased intestinal neoplasia. The complement fragment C5a acts as the trigger for inflammation and intestinal tumorigenesis. High-fat diet induces complement activation and generation of C5a, which in turn induces the production of proinflammatory cytokines and expression of proto-oncogenes. Pharmacological and genetic targeting of the C5a receptor reduced both inflammation and intestinal polyposis, suggesting the use of complement inhibitors for preventing diet-induced neoplasia. IMPLICATIONS:This study characterizes the relations between diet and metabolic conditions on risk for a common cancer and identifies complement activation as a novel target for cancer prevention. Mol Cancer Res; 14(10); 953-65. ©2016 AACR.

@article{Doerner:2016dta, abstract = {Obesity and related metabolic disturbances are closely associated with pathologies that represent a significant burden to global health. Epidemiological and molecular evidence links obesity and metabolic status with inflammation and increased risk of cancer. Here, using a mouse model of intestinal neoplasia and strains that are susceptible or resistant to diet-induced obesity, it is demonstrated that high-fat diet-induced inflammation, rather than obesity or metabolic status, is associated with increased intestinal neoplasia. The complement fragment C5a acts as the trigger for inflammation and intestinal tumorigenesis. High-fat diet induces complement activation and generation of C5a, which in turn induces the production of proinflammatory cytokines and expression of proto-oncogenes. Pharmacological and genetic targeting of the C5a receptor reduced both inflammation and intestinal polyposis, suggesting the use of complement inhibitors for preventing diet-induced neoplasia. IMPLICATIONS:This study characterizes the relations between diet and metabolic conditions on risk for a common cancer and identifies complement activation as a novel target for cancer prevention. Mol Cancer Res; 14(10); 953-65. {\textcopyright}2016 AACR.}, added-at = {2017-12-08T05:18:19.000+0100}, affiliation = {Department of Genetics, Case Western Reserve University, Cleveland, Ohio.}, author = {Doerner, Stephanie K and Reis, Edimara S and Leung, Elaine S and Ko, Justine S and Heaney, Jason D and Berger, Nathan A and Lambris, John D. and Nadeau, Joseph H}, biburl = {https://www.bibsonomy.org/bibtex/2e1efcba2dd22f28e1c7d3b00daa943f9/lambris}, date-added = {2017-12-08T04:15:42GMT}, date-modified = {2017-12-08T04:17:38GMT}, doi = {10.1158/1541-7786.MCR-16-0153}, interhash = {9fb6f3bd8972449080bd14f70825af95}, intrahash = {e1efcba2dd22f28e1c7d3b00daa943f9}, journal = {Molecular cancer research : MCR}, keywords = {imported}, language = {English}, month = oct, number = 10, pages = {953--965}, pmcid = {PMC5330314}, pmid = {27535705}, rating = {0}, timestamp = {2017-12-08T05:18:19.000+0100}, title = {{High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity.}}, uri = {\url{papers3://publication/doi/10.1158/1541-7786.MCR-16-0153}}, url = {http://mcr.aacrjournals.org/cgi/doi/10.1158/1541-7786.MCR-16-0153}, volume = 14, year = 2016 }