A red meat-derived glycan promotes inflammation and cancer progression

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.

Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival

“…In addition, as elicited anti-Neu5Gc antibodies recognize different patterns of Neu5Gc epitopes than "natural" ones (26) and their presence results in increased long-term exposure of Neu5Gc-positive ECs to these antibodies, they may trigger a chronic inflammation of graft vascular walls, as further discussed below. Indeed, in Cmah KO mice, an animal model unable to biosynthesize Neu5Gc, similarly to humans, it has been demonstrated that anti-Neu5Gc antibodies can stimulate chronic inflammation in dietary Neu5Gc-charged tissues (36). A number of types of antibody specificities against rabbit IgG were explored.…”

Detection of the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and anti-Neu5Gc antibodies within reproductive tracts of male and female infertility subjects

“…There is also experimental evidence for Neu5Gc acting as a xeno-auto antigen capable of exacerbating an inflammatory reaction within vasculature endothelium [15]. A recent study proved that the dietary xenoglycan Neu5Gc causes increased cancer via systemic inflammation in a mouse model [16]. More sensitive detection methods have provided evidence for widespread anti-Neu5Gc antibodies in most humans tested, including IgM, IgA, and IgG antibodies [17].…”

Altered expression of ganglioside GM3 molecular species and a potential regulatory role during myoblast differentiation

“…Subsequently, Neu5Gc-containing glycoconjugates are hydrolyzed to Neu5Gc monosaccharides in lysosomes. Neu5Gc monosaccharides are transported to cytosol, and Neu5Gc is activated to CMP-Neu5Gc by CMP-sialic acid synthetase in the nucleus (21)(22)(23). (ii) In the de novo synthesis pathway, sialic acid Neu5Ac is synthesized in cytosol and activated to CMPNeu5Ac in the nucleus, and CMP-Neu5Ac is subsequently converted to CMP-Neu5Gc by the enzyme CMP-Neu5Ac hydroxylase (CMAH) in cytosol (24,25).…”