A red meat-derived glycan promotes inflammation and cancer progression

A red meat-derived glycan promotes inflammation and cancer progression

1. Annie N. Samraja,1, 
2. Oliver M. T. Pearcea,1, 
3. Heinz Läublia, 
4. Alyssa N. Crittendena, 
5. Anne K. Bergfelda,
6. Kalyan Bandaa, 
7. Christopher J. Gregga, 
8. Andrea E. Bingmana, 
9. Patrick Secresta, 
10. Sandra L. Diaza,
11. Nissi M. Varkia,b, and 
12. Ajit Varkia,c,2

Author Affiliations

1. Edited by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, and approved November 25, 2014 (received for review September 18, 2014)

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Significance

We present an unusual mechanism for the well-known association between red meat consumption and carcinoma risk involving the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc). We first evaluate the Neu5Gc content of various foods to show that red meats are particularly rich in orally bioavailable Neu5Gc and then investigate human-like Neu5Gc-deficient mice fed this form of Neu5Gc. When such mice were challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Long-term exposure to this combination resulted in a significantly higher incidence of carcinomas (five-fold increase) and an association with Neu5Gc accumulation in the tumors. Similar mechanisms may contribute to the association of red meat consumption with other diseases, such as atherosclerosis and type 2 diabetes, which are also exacerbated by inflammation.

Abstract

A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of “red meat” of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption.

• red meat and cancer
 
• N-glycolylneuraminic acid
 
• tumor-associated inflammation
• tumor-associated carbohydrate antigen
 
• xenosialitis

Footnotes

• 1A.N.S. and O.M.T.P. contributed equally to this work.
• 2To whom correspondence should be addressed. Email: a1varki@ucsd.edu.

• Author contributions: A.N.S., O.M.T.P., A.N.C., K.B., N.M.V., and A.V. designed research; A.N.S., O.M.T.P., H.L., A.N.C., A.K.B., K.B., C.J.G., A.E.B., P.S., S.L.D., and N.M.V. performed research; A.N.S., O.M.T.P., H.L., and A.K.B. analyzed data; and A.N.S., O.M.T.P., H.L., and A.V. wrote the paper.
• Conflict of interest statement: A.V. and N.M.V. are cofounders of and advisors to SiaMab Therapeutics, Inc., which has licensed University of California, San Diego technologies related to anti-Neu5Gc antibodies in cancer.
• This article is a PNAS Direct Submission.
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1417508112/-/DCSupplemental.