There is a wide recognition that the over-consumption of “red meat” increases the probability of the development of colorectal cancer in humans, in contrast to its effect on other carnivores. Dr Ajit Varki’s team in the Department of Cellular and Molecular Medicine at the University of California, San Diego (UCSD) suggest the answer is a sugar molecule, Neu5Gc, enriched in red meats of mammalian origin. The work of Dr Varki’s team is published in the Proceedings of the National Academy of Sciences (PNAS).
For cancer to gain a foothold multiple genetic changes to certain regions of the genome are required. Each change expands the population of altered cells, creating a larger target pool for subsequent genetic changes. In normal circumstances, controlling the number of cells that divide, versus the number that are apoptosed (reduced and eventually engulfed by other cells), tightly regulates this number. In healthy colonic tissue, stem cells divide and differentiate as they move up into the villus from the crypt. At this point there is a fine balance between the proliferation of stem cells and their terminal differentiation into villus cells. Changes to this process results in abnormal, sustained cell growth – the most fundamental trait of cancer cells. It is thought this might be why the colon appears so prone to cancer.
Colorectal cancer is a progressive malignancy where successive genetic events result in metastasis (spreading to other areas of the body, mainly lungs, liver and lymph nodes). It initiates as small, benign polyps – smaller than 1 cm in diameter – before progressing to a metastatic cancer over a period of 10-35 years.
The hallmarks of cancer, such as resisting apoptosis and inducing the formation of new blood vessels, are underpinned by genomic instability as well as inflammation, driven by cells of the immune system. Some of these cells serve to promote tumour progression. Varki’s team found the N-glycolylneuraminic acid (Neu5Gc) molecule to be bio-available, meaning it can distribute to tissues throughout the body via the bloodstream. By studying the effects of Neu5Gc in human-like mice genetically engineered to be deficient in their own Neu5Gc sugar, the scientists gained an insight to its mechanistic action.
Neu5Gc is a nonhuman sialic acid molecule found in most mammals. This molecule is not naturally occurring in humans. Consequently, humans produce antibodies to target the molecule when it enters the body because the immune system identifies it as foreign. The scientists discovered that when fed with Neu5Gc long-term, these mice are five times more likely to develop cancerous tumours, finding high concentrations of Neu5Gc in them. They found that the treated mice developed systemic inflammation caused by antibodies reacting to the sugar molecule.
To date, most evidence of red meat’s link to cancer probability has been through statistical association in meta-data, rather than empirical evidence. Lead author Dr Ajit Varki states, “Until now, all of our evidence linking Neu5Gc to cancer was circumstantial or indirectly predicted from somewhat artificial experimental setups. This is the first time we have directly shown that mimicking the exact situation in humans – feeding non-human Neu5Gc and inducing anti-Neu5Gc antibodies – increases spontaneous cancers in mice.”
Further work is necessary to identify the precise pathways by which Neu5Gc is absorbed by tissues, as well as work into potential therapeutic approaches to counteract its effects. Additionally, this work may be pathologically relevant to other inflammation-driven conditions thought to be associated with the over-consumption of red meat.
Transducing immunological effects from rodents to humans is rarely straightforward. As Varki also states, “The final proof in humans will be much harder to come by”.
It should be noted that when consumed in moderation, as part of a balanced dietary intake, red meat is generally considered a healthy source of nutritional protein.
How might similar discoveries influence the food industry and health standards agencies?