Involvement of a Non-Human Sialic Acid in Human Cancer

Abstract

Sialic acids are common monosaccharides that are widely expressed as outer terminal units on all vertebrate cell surfaces, and play fundamental roles in cell–cell and cell–microenvironment interactions. The predominant sialic acids on most mammalian cells are N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac). Neu5Gc is notable for its deficiency in humans due to a species-specific and species-universal inactivating deletion in the CMAH gene encoding the hydroxylase that converts CMP-Neu5Ac to CMP-Neu5Gc. However, Neu5Gc is metabolically incorporated into human tissues from dietary sources (particularly red meat), and detected at even higher levels in some human cancers. Early life exposure to Neu5Gc-containing foods in the presence of certain commensal bacteria that incorporate dietary Neu5Gc into lipooligosaccharides can lead to generation of antibodies that are also cross-reactive against Neu5Gc-containing glycans in human tissues (“xeno-autoantigens”). Such anti-Neu5Gc “xeno-autoantibodies” are found in all humans, although ranging widely in levels among individuals, and displaying diverse and variable specificities for the underlying glycan. Experimental evidence in a human-like Neu5Gc-deficient Cmah−/−mouse model shows that inflammation due to “xenosialitis” caused by this antigen–antibody interaction can promote tumor progression, suggesting a likely mechanism for the well-known epidemiological link between red meat consumption and carcinoma risk. In this review, we discuss the history of this field, mechanisms of Neu5Gc incorporation into tissues, the origin and specificities of human anti-Neu5Gc antibodies, their use as possible cancer biomarkers, implications of xenosialitis in cancer initiation and progression, and current and future approaches toward immunotherapy that could take advantage of this unusual human-specific phenomenon.

A red meat-derived glycan promotes inflammation and cancer progression

“…In this regard, we have suggested an unusual human-specific mechanism, involving inflammation associated with metabolic incorporation of a nonhuman sialic acid, N-glycolylneuraminic acid (Neu5Gc), and interaction with circulating anti-Neu5Gc antibodies (16)(17)(18)(19). Despite the fact that humans are genetically unable to produce Neu5Gc, this molecule is detectable on surfaces of human epithelia and endothelia, and in higher amounts in malignant tissues (20).…”

SNAT7 is the primary lysosomal glutamine exporter required for extracellular protein-dependent growth of cancer cells

“…For instance, external free sialic acids enter cells through pinocytosis and lysosomal export by the sialic acid transporter sialin (8,9). This two-step indirect route accounts for the metabolic incorporation of the dietary, nonhuman sialic acid N-glycolylneuraminic acid into human cell glycans (10). Recently, lysosomes have been similarly shown to participate in an "opportunistic" nutrition route of cancer cells when free amino acids are scarce in their environment (11).…”

On the apparent rarity of epithelial cancers in captive chimpanzees

“…With regard to one particular risk factor for human carcinomas, our recent work suggests that it is human-specific. In this instance, the nonhuman sialic acid Neu5Gc is metabolically incorporated from red meats (lamb, pork and beef ) into human epithelia and endothelia, and therein interacts with circulating anti-Neu5Gc antibodies [39]. Our evidence suggests that the resulting chronic inflammation may contribute to cancer progression [39,40].…”