Lectin‐Like Properties of Human Antibodies Against the Red Meat‐derived Antigen N‐Glycolylneuraminic Acid: A Mitogenic Factor Promoting Carcinoma Growth

Considerable epidemiological data has shown that human susceptibility to various carcinomas (particularly colorectal cancer) is strongly impacted by diet, especially by the consumption of red meat (foods of mammalian origin). There are many proposed mechanisms for the cancer‐promoting effects of red meat including generation of mutagens by grilling or addition of nitrates, and free‐radical generation by heme iron. However, the grilling and nitrate addition factors also apply to poultry and fish (which are not associated with cancer risk), and the heme iron theory is not conclusively proven. Also unexplained is the fact that other carnivores do not seem to share this red meat related risk. Our group has recently discovered a novel human‐specific mechanism involving the consumption of a non‐human sialic acid N‐glycolylneuraminic acid (Neu5Gc), which is enriched in red meats. We have reported that despite the fact that humans are genetically unable to produce Neu5Gc, this molecule can be metabolically incorporated and expressed on the cell surface glycans of human carcinomas after dietary intake. Such Neu5Gc containing glycans interact with circulating anti‐Neu5Gc antibodies, leading to an inflammatory response (xenosialitis), which can increase tumor incidence in human‐like Neu5Gc‐deficient mice that have circulating anti‐Neu5Gc antibodies. These antibodies naturally exist at variable concentrations in all humans. Since anti‐Neu5Gc antibodies can interact with any cell surface glycans containing Neu5Gc, we considered the possibility that these antibodies may also have lectin‐like activity by cross‐linking multiple surface molecules, with pleiotropic effects on cell signaling during interaction with tumor cells expressing Neu5Gc. To test this hypothesis, human colorectal cell lines were fed with Neu5Gc and incubated with human serum samples containing high levels of anti‐Neu5Gc antibodies. We observed that incubation of colorectal cells with the serum samples led to surface deposition of anti‐Neu5Gc IgG and IgM antibodies and complement in Neu5Gc‐fed but not in unfed cells. The antibody and complement deposition induced cross‐linking of cell surface glycoproteins like Muc‐1 and increased phosphorylation of S6 ribosomal protein. Corroborating these findings, our preliminary data suggests that anti‐Neu5Gc antibodies have mitogenic properties that can promote proliferation of colorectal cancer cells expressing Neu5Gc, via a mechanism similar to that of growth factors. Our results show for the first time the lectin‐like activity of human anti‐Neu5Gc antibodies as a mechanism for the promotion of carcinoma growth associated with red meat consumption. Support or Funding Information Program Science Without Borders ‐ Conselho Nacional de Aperfeicoamento de Pessoal de Nivel Superior (Capes) BEX‐9254‐13‐7‐ Brazil to FAS and NIH R01GM32373 to AV.