The Mechanistic Action Of MDSC On The Development Of UC-related Colorectal Cancer

Objective:To uncover the factors which are key for MDSC induction in the progression of colitis to cancer and investigate the contribution of MDSC to ulcerative colitis malignant transformation and underlying mechanisms, which may be potential targets for the development of novel regimens to treat colitis-aasociated cacner in clinic.Methods:Colitis-associated cancer (CAC) was established in Balb/c strains and different stages of CAC progression were installmented. MDSC proportion in peripheral organs and lesions was examined by flow cytometry. Several cytokines expression in the supernatants of colonic tissues was determined by ELISA at different timepoint after the initiation of DSS drinking. The microarray was performed to detect differently expressed genes in MDSC from spleen of CAC-bearing mice compared to naive counterparts. Sorafenib or neutralizing anti-VEGF monoclonal antibody was used to block VEGF signaling. The proportion of MDSC in lesions and histopathology was detected in CAC-bearing mice with blockade of VEGF signaling or not.Result:Murine CAC model was established successfully.1month and3month after the initiation of DSS drinking was verified as the early and late stage of CAC respectively, according to several parameters. Increased number of MDSC was observed in the progression of CAC. This was more significant in lesions of neoplasia [early stage of CAC (1.32±0.04)%, late stage of CAC (3.08±0.29)%vs control (0.30±0.18)%, p<0.05]. These cells highly expressed arginase-1and inducible nitric oxide synthase. Accordingly, the colonic contents of L-arginine in CAC-bearing mice were much lower than controls [(4.22±0.17) μg/ml,(2.95±1.08) μg/ml vs (4.41±0.16)μg/ml, p<0.05], which might lead to the suppression of effector T cell proliferation. The microarray found1154differential expressed genes in CAC-bearing mice compared to naive counterpart, up642, down512. Further analysis found the MDSC closely related genes and pathways, and there is a noteworthy tumor suppressor gene pdgfrl. Furthermore, VEGF expression in the lesions of CAC-bearing mice was elevated significantly [early stage of CAC (1170±94.43) pg/ml, late stage of (1117±71.92) pg/ml vs control (877.6±31.67) pg/ml, p<0.05]. The treatment of Sorafenib or anti-VEGF dramatically reduced accumulation of MDSC in the lesions thereby retard the CAC progression.[Sorafenib treatment group:control (0.74±0.17)%, CAC+Sorafenib (0.56±0.12)%vs CAC (2.81±0.39)%; VEGF mAb treatment group:control (0.24±0.02)%, CAC+VEGFmAb (2.09±0.05)%vs CAC (3±0.07)%, p<0.01].Conclusion:MDSCs have a disease-promoting role in the progression of colitis to cancer. VEGF plays a pro-tumor role in CAC formation, which is partially attributed to inducing accumulation of MDSC in colonic tissues, the latter actively suppress anti-tumor immune responses and support CAC outgrowth. The pdgfrl is likely to contribute to the abnormal proliferation of MDSC.