High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity

Mol Cancer Res. 2016 Oct;14(10):953-965. doi: 10.1158/1541-7786.MCR-16-0153. Epub 2016 Aug 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Complement Activation
  • Complement C5a / metabolism*
  • Cytokines / metabolism*
  • Diet, High-Fat / adverse effects*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intestinal Neoplasms / chemically induced
  • Intestinal Neoplasms / immunology*
  • Intestinal Neoplasms / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / chemically induced
  • Obesity / chemically induced
  • Obesity / immunology*
  • Obesity / metabolism
  • Proto-Oncogenes


  • Cytokines
  • Complement C5a