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origin. Major sources appear to be red meats (i.e., lamb, pork, and beef) and, to a lesser extent, milk products (Tangvoranuntakul et al., 2003). In contrast, Neu5Gc is not found in poultry, and amounts in fish seem to be low (Tangvoranuntakul et al., 2003). Thus, within limits of current analyses, the primary source of human tissue Neu5Gc appears to be foods of mammalian origin. In this regard, many epidemiological studies have shown an association of red meat ingestion with increased risk for various diseases, including carcinomas (Fraser, 1999; Wiseman, 2008; Sinha et al., 2009), atherosclerosis (Fraser, 1999; Sinha et al., 2009), type-2 diabetes (Song et al., 2004), and age-dependent macular degeneration (Chong et al., 2009). Although there are other theories for how red meat consumption aggravates these diseases, most of these notions (other than the role of saturated fats in atherosclerosis) are unproven. We suggest that metabolic incorporation of dietary Neu5Gc in the face of anti-Neu5Gc antibodies contributes to red meat aggravation of diseases by stimulating chronic inflammation (Hedlund et al., 2008; Pham et al., 2009).

ANTI-Neu5Gc ANTIBODIES ENHANCE GROWTH OF Neu5Gc-POSITIVE TUMORS IN Neu5Gc-NULL MICE

Human carcinomas efficiently accumulate dietary Neu5Gc for multiple reasons, including up-regulation of lysosomal Sia transport by hypoxia (Yin et al., 2006) and enhanced macropinocytosis caused by growth factor activation. This accumulation occurs in the face of anti-Neu5Gc antibody responses, which are enhanced in such patients (Malykh et al., 2001). This combination suggests an immune reaction insufficient to kill the tumor that may, instead, stimulate it. Indeed, antibody-mediated inflammation is known to facilitate tumor progression by recruiting inflammatory cells, which stimulate angiogenesis and provide growth factors (Tan and Coussens, 2007). We mimicked the human situation using Neu5Gc-null mice bearing a syngeneic mouse tumor line that expresses low levels of Neu5Gc, similar to human tumors. Indeed, passively transferred anti-Neu5Gc immune serum from syngeneic Neu5Gc-null mice increased tumor growth rates associated with inflammation and angiogenesis (Hedlund et al., 2008), and these effects were blocked by a COX-2 inhibitor, a drug type that reduces human tumor incidence (Hedlund et al., 2008). Of course high levels of these antibodies may instead kill tumor cells, and it is possible that persons with very high anti-Neu5Gc antibodies are protected from some cancers. Indeed, can we harness human anti-Neu5Gc antibodies to target human cancers specifically?



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