The Preventive Effect And Mechanism Of Mannose On Colitis-associated Colorectal Tumorigenesis In Mice

The prevention of colorectal cancer is an urgent clinical problem,and targeting the tumor associated-macrophages polarization is a new direction for colorectal cancer prevention.The latest research has shown that mannose has various biological activities.For example,mannose could impair tumor growth.But,the concentration of plasma mannose after oral administration is much lower than the concentration of mannose to inhibit tumor growth.This result suggests that there may be other mechanisms for the anti-tumor function of mannose.Therefore,this study investigated the effects of mannose on experimental colitis associated-colorectal tumorigenesis,and then explored the possible mechanisms of mannose on preventing colorectal cancer.The main research contents of the study are as follows:First,an experimental colitis-associated colorectal cancer mouse model was constructed to research the preventive effect of mannose on colorectal cancer.The results showed that mannose effectively attenuated colitis-associated colorectal tumorigenesis.From the apparent data of each group of mice,mannose significantly improved survival rate and body weight of colorectal cancer mice,and effectively prevented the development of colorectal tumors.The mainly results are as follows: compared with the model group,the number of tumors in the mannose treatment groups decreased by 48.35%(p<0.001),and the proportion of large grade tumors(>3 mm)decreased from 24.11% to 10.53%.In addition,mannose significantly reduced the colon weight/mm,spleen index,and relative m RNA expression of pro-inflammatory cytokines and alleviated histopathological lesions.Then,a mouse model of ulcerative colitis was established to study the effects of mannose on the early inflammation of colorectal cancer.The results showed that mannose alleviated weight loss,colon shortening,inflammatory infiltration of colonic mucosa in colitis mice.The details are as follows: compared with the model group,the colon length of mice in low-dose and high-dose mannose treatment groups increased by 10.32%(p<0.001)and 20.46%(p<0.001).Respectively,mannose decreased the production of inflammatory cytokines in colon tissue.Mannose also significantly improved oxidative stress injury and gut barrier damage in colitis mice.In addition,we explored the effects of mannose on the malignant transformation of epithelial cells and the malignant proliferation characteristics of tumor cells.The different development stages of colorectal tumors were simulated in vitro.The results showed that mannose could not affect the growth factor induced malignant transformation of epithelial cells,the proliferation of human colon tumor cell lines(HCT116,HT29,and SW620),and mouse colon tumor cell line CT26.It also did not affect the non-anchored growth ability of colon tumor cells(HCT116,HT29).The above results indicated that mannose did not directly affect the malignant features of colon tumor cells.It attenuated colorectal cancer possibly through some indirect effects.Finally,we found that mannose could inhibit the production of lactate in colon tumor cells.Based on tumor-derived lactate could induce the polarization of tumor-associated macrophages,we used human colon tumor cell HCT116 co-incubated with macrophages to construct tumorassociated macrophages in vitro,to explore the effects of mannose on the polarization of tumor associated-macrophages.The results suggested that mannose impaired the production of lactate by inhibiting HKⅡ and regulated tumor-derived lactate-induced polarization of tumorassociated macrophages.The details are as follows: mannose significantly inhibited the m RNA expression of tumor-associated macrophage marker(VEGF and Arg-1)in vitro.At the same time,mannose reduced the number of tumor-associated macrophages in tumor tissues of colorectal cancer mice.The reason is that mannose inhibited the expression of HKⅡ.The lactate produced by HCT116 cells is reduced.Tumor-derived lactate induced the polarization of tumor associated macrophages was regulated.This study revealed that mannose could prevent colitis-associated colorectal cancer by inhibiting inflammation and tumor-associated macrophages polarization,and provided a new theoretical basis for mannose to prevent colorectal cancer.