| The relationship between inflammation and tumor gradually becomes the hot spot area in recent years. A large number of clinical and basic research data show that inflammation can promote the occurrence of tumor. Colitis-associated cancer (CAC), one of the Colorectal Cancer (CRC) subtype associated with inflammatory bowel disease (IBD), is difficult to treat, and has high mortality rate. More than20%of IBD patients develop CAC within30years of disease onset, and50%of these will die from CAC. Some of the essential stages of cancer development, including formation of atypical hyperplasia, adenomas, and carcinomas, are similar between sporadic CRC and CAC.There are a number of inflammatory cytokines signaling pathways involved in the process as well as a variety of mutations of oncogenes and tumor suppressor genes. These inflammatory cytokine signaling pathways together with immune cells play important role in development of CAC. Despite its pathogenic importance, the mechanisms responsible for the transformation of IBD to CAC are still poorly understood due to the complexity of intestinal environment and its interaction with immune systems.Th17cell and its derived cytokines are supposed to play an important role in the development of IBD and CAC. In addition, Myeloid-derived suppressor cell (MDSC) also contributes to the development of IBD and CAC correlated with Th17. Therefore, exploring the interplay and relationship among Th17, MDSC, intestinal epithelial cells, cytokines and chemokines may provide us an important clue for understanding the pathology of IBD to CAC. By using the mouse CAC disease model and immunodeficiency animals, our study aims to explore the cytokine networks for regulation of the immune cells and its role in the development of CAC.In the present study, Azoxymethane-Dextran sodium sulfate (Aom-Dss, AD) induced mouse CAC model can simulate the evolution process of colorectal cancer. Increased infiltration of T cells and B cells, MDSC and tumor associated macrophages (TAM) was positively related to the disease process. The recruitment of MDSC and TAM into the inflamed tissues could be partially inhibited by lack of lymphocytes, which could also alleviate the inflammation status and reduced cancer incidence. Compared with Severe combined immunodeficiency-AD (SCID-AD) group, there are higher expressions of Granulocyte colony-stimulating factor (G-CSF), IL-17A, Chemokine (C-X-C motif) ligand1(CXCL1) and Chemokine (C-X-C motif) ligand2(CXCL2) mRNA in C57-AD group through Real-time PCR and protein chip assay. Histologically, G-CSF was expressed by intestinal epithelial cells and colocalized with intestinal epithelial cells detected by immunefluorescence. Furthermore, intestinal primary cells could express high levels of G-CSF, CXCL1and CXCL2mRNA induced by exogenous IL-17A.The function of G-CSF is to recruit MDSC from bone marrow to inflamed tissues and stabilize the MDSC function, promote cell proliferation and resistance to apoptosis. The MDSC sorted from colon tissues of CAC mouse could express high levels of IL-6, IL-1β and iNOS, which could induce epithelial damage and promote malignant transformation. Next, we reconstituted SCID mice with purified T cells and found recover of MDSC in the inflamed tissues and re-expression of G-CSF. These results indicate that IL-17A/G-CSF axis could recruit MDSC into inflamed tissues through the regulation of Thl7, epithelial cells and MDSC functions, which contribute to the development of CAC. Moreover, the secretion of CCL2by B cells could recruit TAM to the inflamed tissue and promote the development of CAC.In summary, these findings indicate that IL-17A/G-CSF axis plays an important role in the regulation of Th17, epithelial cells and MDSC interaction and the development of CAC. Our findings provide a new avenue of cancer associated inflammation and a potential therapeutic target for colitis-associated cancer. |
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