The Relationship Between Macrophage And Tumorigenesis In The Aging Process

Cancers are aging-related diseases.The incidence of cancers increases with age.Besides telomere damage,epigenetic disorder and accunulation of DNA damage,immune microenvironment is closely related to tumorigenesis.Aging can lead to a series of change in the immune system,and imbalanced pro-inflammatory/anti-inflammatory microenvironment may promote the growth of tumors.Macrophages can regulate the immune microenvironment through their own phagocytosis and secretion of cytokines.It has been reported that aging can increase oxidative stress at resting level of bone marrow macrophages and its pro-inflammatory/anti-inflammatory ratio.Moreover,the ability of aging macrophages to polarize to elassical pro-inflammatory or anti-inflammatory phenotypes is deficient.However,the relationship between macrophages and tumorigenesis during aging is still unclear.In this study,we first analyzed the relationship between macrophage infiltration and survival of patients with colon cancer.The results showed that high macrophage infiltration was associated with shorter overall survival.Subsequently,the concentration of macrophage-related cytokines in the serum of young and old mice was detected by cytokine microarray.It was found that there were differences in macrophage-related cytokines between young and old mice.In order to explore the function of macrophages in different age groups,bone marrow and peritoneal macrophages from young and old individuals were isolated.After stimulation with tumor supernatant,TAMs were mixed with colon cancer cell line CT26(1:10)and then subcutaneously inoculated into nude mice.The results showed that both bone marrow-derived macrophages and peritoneal macrophages could enhance the growth of CT26 xenograft tumors.And peritoneal macrophages from aged mice had stronger tumorigenicity than young.To investigate the possible mechanism,we detected the expression levels of some macrophage related cytokines by qRT-PCR.After stimulation by the supermatant of tumor cells,the expression of 116,Mrc4 and Ccl2 were significantly up-regulated in the peritoneal macrophages of the aged mice compared with those of young mice.Next,we explored the response of macrophages to drug treatment.Chidamide,a HDAC inhibitor,inhibited the growth of CT26 xenograft tumors.CT26 mixed with TAMs(10:l)from young or aged mice were subcutaneously inoculated into nude mice,after tumor formation,mice were treated with Chidamide.The results showed that the xenograft tumors mixed with TAMs from old mice were more stronglyinhibited..Subsequently,we treated macrophages with Chidamide and detected the expression of related cytokines.The results showed that the expressions of Nos2,Tnf,I11beta,114,1110,1112 and 1123 in macrophages from aged mice were significantly higher than thosefrom young mice.In conclusion,our results suggest that TAMs derived from aged mice could promote tumor growth more stronglythan those from young mice.But the xenograft tumors mixed with TAMs from old mice were more sensitive to Chidamide.The exact mechanism needs to be further explored.