N-glycolylneuraminic acid (Neu5Gc) is a non-human sialic acid derived from the diet (primarily red meat) that can be metabolically incorporated into human tissues despite being an antigen. Since this incorporation occurs in the face of circulating anti-Neu5Gc antibodies, we hypothesized that this generates an antibody-antigen reaction and leads to inflammation termed “xenosialitis”. Although red meat consumption is prominently associated with cancer development, pathological mechanisms behind this link are yet to be conclusively proven. The purpose of our research is to investigate the relationship between “xenosialitis”, inflammation and cancer. We used a Cmah null mouse model (mimicking the human lack of Neu5Gc) to provide evidence for such inflammation and cancer promotion. Anti-Neu5Gc antibodies were generated by immunizing Cmah null mice, with chimpanzee red blood cell membranes, or with human red blood cell membranes as controls. Pooled immune or control sera were repeatedly adsorbed with human red blood cells, and the resulting polyclonal antisera passively transferred into additional Cmah null mice that were on a diet with or without Neu5Gc. Mice fed with Neu5Gc and injected with anti-Neu5Gc antibodies showed dose-dependent elevation in acute phase proteins (Serum Amyloid A and Haptoglobin) in the serum as compared to controls. Such C57BL/6 mice are prone to developing hepatic adenomas and occasional carcinomas. Cmah null but not wild-type C57BL/6 mice immunized with chimpanzee red blood cell membranes and fed with Neu5Gc developed a higher frequency of hepatocellular cancer and liver histology showed Neu5Gc accumulation and foci of inflammation. In conclusion, Neu5Gc that has metabolically incorporated into tissues from the diet interacts with anti-Neu5Gc antibodies, generating xenosialitis. Potential correlations of human anti-Neu5Gc antibody levels with red meat consumption and cancer risk are being investigated. Methods to flush out the xenogenic Neu5Gc are being pursued. Similar mechanisms may be operative in other chronic inflammatory processes in diseases epidemiologically associated with red meat consumption, such as atherosclerosis.
Citation Format: Annie N. Samraj, Heinz Laubli, Oliver Pearce, Patrick Secrest, Andrea E. Garcia-Bingman, Nissi Varki, Ajit Varki. A diet-derived sialic acid promotes inflammation and hepatocellular cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-156. doi:10.1158/1538-7445.AM2014-LB-156