Siglec-E functions as a brake for intestinal inflammation to protect from colitis-associated cancer 2260102

Abstract

Abstract Introduction The lifetime risk for colorectal cancer (CRC) in the United States is approximately 4%. Individuals with Inflammatory Bowel Disease, including Ulcerative Colitis and Crohn’s Disease, have a substantially increased risk of developing colorectal cancer. Siglecs (sialic acid immunoglobulin lectin-like proteins) are a family of receptors that regulates the immune response. Siglec-E is a mouse inhibitory receptor that is primarily expressed by innate cells. While others have demonstrated that Siglec-E KO mice reject tumors faster in multiple tumor models, we have found that colorectal cancer is accelerated in Siglec-E KO mice. Here we aim to investigate the role of Siglec-E in immune homeostasis, inflammation and colorectal cancer development. Methods We used two models of colorectal cancer to assess the role of Siglec-E in tumorigenesis: TS4-cre LSL KRASG12D APClox468/wt (TAR mice) and the DSS/AOM model of colitis-associated cancer. Colons were prepared by separating lamina propria (LP) and epithelial (EP) fractions for flow cytometry. 2cm sections were taken from the middle of colons to generate lysates for ELISA. DSS was administered to WT and Siglec-E KO mice to assess the susceptibility to intestinal inflammation. H&E and IHC for PCNA were performed on colonic tissue from experiments. Results We have found that in both the spontaneous and DSS induced models of CRC, Siglec-E KO mice grow more tumors than WT mice. Siglec-E KO mice have an exquisite susceptibility to DSS induced inflammation and reduced number and proportion of neutrophils after treatment. Lastly, we have found that Siglec-E KO mice at baseline have increased VEGF-A in the colon. Conclusion Siglec-E has a critical role in regulating immune homeostasis in the colon. Siglec-E functions as a brake for intestinal inflammation which protects from the development of colorectal cancer. Funding Source This research was funded by NIH grant CA243545-01A1 (VSS), NIH T32 AI170478 (VSS/BM), and and grant R25 GM055252-26 Deans fellowship: Initiative for maximizing student development (IMSD). Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)