Abstract 5055: Expression of Tn and SialylTn tumor antigens in intestinal epithelia in APC-mutant mice promotes colorectal carcinogenesis and progression

Abstract

Abstract Colorectal cancer (CRC) is a leading cause of cancer deaths in the Western world, and several different animal models for CRC have been established to understand its initiation, progression, and metastasis. Mice with mutations in APC (APCm) is widely accepted in the field because APC is the predominant mutated gene in human CRC. Mice carrying APCm only develop multiple intestinal neoplasia, but not carcinoma. Importantly, emerging evidence shows that tumor associated carbohydrate antigens, Tn and sialylTn (STn) appear at an early stage of colon carcinogenesis, and are associated with progression and metastasis. However, the molecular mechanisms underlying the role of Tn/STn antigens in CRC tumorigenesis and progression are unknown. We identified a novel X-linked gene Cosmc (C1GalT1C1) which encodes a molecular chaperone Cosmc regulating O-glycosylation through assisting correct folding of core 1 β3-galactosyltransferase (T-synthase, C1GalT1). T-synthase is the key enzyme that converts Tn antigen to normal core 1 O-glycans on glycoproteins in all animal cells. Cosmc mutations lead to loss of T-synthase activity and resultant expression of Tn/STn antigens in human carcinoma cells and in other diseases. Moreover, in our study, intestinal epithelial cell (IEC)-specific Cosmc-knockout (IEC-Cosmc-KO) mice spontaneously developed invasive tumors mainly in the rectum from 3-12 months of age through complex pathways. To further investigate the role of Tn/STn antigens in CRC formation, progression and metastasis in a context of APC mutations, we generated IEC-Cosmcnull:APC-/+ (double-knockout, DKO) by gene targeting. Totally, 22 DKO mice (13 male and 9 female) and similar numbers of control mouse groups (APC-KO, Cosmc-KO and WT) were generated. Among them, the DKO male and female mice grew slower companied with stress signs and some mortalities around 3-4 months of age. Importantly, both APC-KO and DKO mice had multiple gross tumors in the small intestine, and all DKO mice had more and larger gross tumors in colorectum while only 15% of APC-KO mice developed tumors with smaller sizes in colon. Consistent with our findings, thickened rectum was observed in Cosmc-KO mice. Furthermore, the enlarged inguinal lymph nodes were also found in the DKO mice. Histology confirmed the Tn/STn expression, as well as adenomas and adenocarcinomas in the DKOs, and adenomas in APC-KOs and Cosmc-KO male mice. The distant metastasis of the CRC was not yet observed in these young DKO-mice, since it may require a longer time to develop. These results clearly indicate that the Cosmc deletion resulted in Tn and STn expression, promotes the colorectal carcinogenesis in APC-mutant mice. We are generating more elder DKO and control mice to continue investigating the role of Tn/STn in CRC progression and metastasis by performing detailed molecular analyses. Citation Format: Yuliang Jiang, Su-Ryun Kim, Shweta Kotian, Sean R. Stowell, Guangyu An, Tongzhong Ju. Expression of Tn and SialylTn tumor antigens in intestinal epithelia in APC-mutant mice promotes colorectal carcinogenesis and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5055.