Dietary intake of the red meat-derived glycan Neu5Gc fuels colorectal cancer through up-regulation of Wnt signaling pathway

Abstract

Colorectal cancer (CRC) is a significant health concern, often linked to western diets, particularly red meat consumption. Several mechanisms, such as the high heme iron content, the formation of N-nitroso compounds (NOCs), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), have been suggested to explain red meat's cancer-promoting effects. However, these factors are also found in fish and poultry, which are not linked to CRC risk. A new hypothesis attributes red meat's impact on CRC to its high content of a nonhuman glycan. While most mammals express N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), humans express only Neu5Ac due to the loss of the CMAH enzyme. A red meat-rich diet leads to the incorporation of Neu5Gc into human cells, triggering an antibody-mediated inflammatory process known as xenosialitis. This study shows that Neu5Gc incorporation into CRC cells activates the Wnt/β-catenin signaling pathway, promoting cell proliferation. In a murine model lacking CMAH, a Neu5Gc-enriched diet induced intestinal polyp growth, with more malignant characteristics. Additionally, Neu5Gc incorporation in intestinal cells increased the expression of genes downstream of Wnt signaling. These findings reveal, for the first time in an in vivo model, a mechanism independent of immune response, where red meat consumption accelerates tumor progression through Neu5Gc incorporation. This activation of the Wnt/β-catenin signaling pathway provides new insight into how red meat consumption may influence CRC progression.