RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis

O Turovskaya, D Foell, P Sinha, T Vogl… - …, 2008 - academic.oup.com
O Turovskaya, D Foell, P Sinha, T Vogl, R Newlin, J Nayak, M Nguyen, A Olsson…
Carcinogenesis, 2008academic.oup.com
Patients with inflammatory bowel diseases are at increased risk for colorectal cancer, but the
molecular mechanisms linking inflammation and cancer are not well defined. We earlier
showed that carboxylated N-glycans expressed on receptor for advanced glycation end
products (RAGE) and other glycoproteins mediate colitis through activation of nuclear factor
kappa B (NF-κB). Because NF-κB signaling plays a critical role in the molecular
pathogenesis of colitis-associated cancer (CAC), we reasoned that carboxylated glycans …
Abstract
Patients with inflammatory bowel diseases are at increased risk for colorectal cancer, but the molecular mechanisms linking inflammation and cancer are not well defined. We earlier showed that carboxylated N-glycans expressed on receptor for advanced glycation end products (RAGE) and other glycoproteins mediate colitis through activation of nuclear factor kappa B (NF-κB). Because NF-κB signaling plays a critical role in the molecular pathogenesis of colitis-associated cancer (CAC), we reasoned that carboxylated glycans, RAGE and its ligands might promote CAC. Carboxylated glycans are expressed on a subpopulation of RAGE on colon cancer cells and mediate S100A8/A9 binding to RAGE. Colon tumor cells express binding sites for S100A8/A9 and binding leads to activation of NF-κB and tumor cell proliferation. Binding, downstream signaling and tumor cell proliferation are blocked by mAbGB3.1, an anti-carboxylate glycan antibody, and by anti-RAGE. In human colon tumor tissues and in a mouse model of CAC, we found that myeloid progenitors expressing S100A8 and S100A9 infiltrate regions of dysplasia and adenoma. mAbGB3.1 administration markedly reduces chronic inflammation and tumorigenesis in the mouse model of CAC and RAGE-deficient mice are resistant to the onset of CAC. These findings show that RAGE, carboxylated glycans and S100A8/A9 play essential roles in tumor–stromal interactions, leading to inflammation-associated colon carcinogenesis.
Oxford University Press