Turovskaya Olga, Foell Dirk, Sinha Pratima, Vogl Thomas, Newlin Robbin, Nayak Jonamani, Nguyen Mien, Olsson Anna, Nawroth Peter P, Bierhaus Angelika, Varki Nissi, Kronenberg Mitchell, Freeze Hudson H, Srikrishna Geetha
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
Carcinogenesis. 2008 Oct;29(10):2035-43. doi: 10.1093/carcin/bgn188. Epub 2008 Aug 9.
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-kappaB). Because NF-kappaB 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-kappaB 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.
炎症性肠病患者患结直肠癌的风险增加，但炎症与癌症之间的分子机制尚未明确。我们之前表明，晚期糖基化终产物受体（RAGE）及其他糖蛋白上表达的羧化N-聚糖通过激活核因子κB（NF-κB）介导结肠炎。由于NF-κB信号传导在结肠炎相关癌症（CAC）的分子发病机制中起关键作用，我们推测羧化聚糖、RAGE及其配体可能促进CAC。羧化聚糖在结肠癌细胞上的一部分RAGE上表达，并介导S100A8/A9与RAGE结合。结肠肿瘤细胞表达S100A8/A9的结合位点，结合导致NF-κB激活和肿瘤细胞增殖。抗羧化聚糖抗体mAbGB3.1和抗RAGE可阻断结合、下游信号传导和肿瘤细胞增殖。在人类结肠肿瘤组织和CAC小鼠模型中，我们发现表达S100A8和S100A9的髓系祖细胞浸润发育异常和腺瘤区域。给予mAbGB3.1可显著减轻CAC小鼠模型中的慢性炎症和肿瘤发生，且RAGE缺陷小鼠对CAC的发生具有抗性。这些发现表明，RAGE、羧化聚糖和S100A8/A9在肿瘤-基质相互作用中起重要作用，导致炎症相关的结肠癌发生。
