Format

Send to

Choose Destination
Mol Cancer Res. 2016 Oct;14(10):953-965. Epub 2016 Aug 17.

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

Author information

1
Department of Genetics, Case Western Reserve University, Cleveland, Ohio.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Pacific Northwest Research Institute, Seattle, Washington.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
5
Department of Genetics, Case Western Reserve University, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
6
Department of Genetics, Case Western Reserve University, Cleveland, Ohio. Pacific Northwest Research Institute, Seattle, Washington. jnadeau@pnri.org.

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. ©2016 AACR.

PMID:
27535705
PMCID:
PMC5330314
DOI:
10.1158/1541-7786.MCR-16-0153
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center