Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment.
DNMT1 is important in maintaining DNA methylation, and participates in the oncogenesis via up- or down-regulation leading to hyper-methylation or hypo-methylation. In the meta and bioinformatic analysis, we found that DNMT1 expression was higher in gastric cancer, compared with normal (p < 0.00001), para-cancerous (p = 0.0004) and dysplasia (p < 0.00001) tissues. DNMT1 up-regulation was associated with gender (OR = 2.27, p = 0.006), differentiation (OR = 0.21, p = 0.01) and TNM stage (OR = 0.31, p = 0.0005). Through TCGA database, DNMT1 overexpression increased gastric cancer risk, but unrelated with clinicopathological parameters and prognosis. Kaplan-Meier plotter showed, an increasing expression of DNMT1 was positive for overall survival rates of patients with stage III and IV (P = 0.044; P = 0.047), N2 and N1-3 phases of lymph node metastasis (P = 0.023; P = 0.032), as well as those with or without distant metastasis (P = 0.0052; P = 0.021). For DNMT1 negative patients, the progression-free survival rates was better in patients with Her2+ or Her2- than positive ones (P = 0.00015; P = 0.031). Besides, surgery alone was effective for the overall survival rates in patients with DNMT1 high expression (P = 0.035), while 5-Fu was useful for those with low expression (P < 0.05). In conclusion, these findings provided evidence that DNMT1 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.
BACKGROUNDIn recent years, the incidence of gastrointestinal (GI) cancer in China has increased annually. Early detection and appropriate therapy are considered to be the key to treat GI cancer. DNMT1 takes an active part in the advancement of GI cancer, which will change as the disease progresses. But its expression characteristics in the dynamic variations of GI carcinogenesis are still unclear.AIMTo investigate the expression characteristics of DNMT1 in different GI diseases.METHODSWe detected the expression of DNMT1 in 650 cases of different GI diseases by immunohistochemistry, including 90 cases of chronic superficial gastritis (CSG), 72 cases of atrophic gastritis with intestinal metaplasia (AG/GIM), 54 cases of low-grade intraepithelial neoplasia (GLIN), 66 cases of high-grade intraepithelial neoplasia (GHIN), 71 cases of early gastric cancer (EGC), 90 cases of normal intestinal mucosa (NIM), 54 cases of intestinal low-grade intraepithelial neoplasia (ILIN), 71 cases of intestinal high-grade intraepithelial neoplasia (IHIN), and 82 cases of early colorectal cancer (ECRC).RESULTSIn the CSG group, all cases showed weakly positive or negative expression of DNMT1. However, in other four groups (AG/GIM, GLIN, GHIN, and EGC), the positive expression rate gradually increased with the severity of the diseases; the negative or weakly positive cases accounted for 55.56% (40/72), 38.89% (21/54), 1.52% (1/66), and 1.41% (1/71), respectively. Besides, the moderately positive cases were 44.44% (32/72), 57.41% (31/54), 80.30% (53/66), and 43.66% (31/71), respectively. The strongly positive cases only existed in the GLIN (3.70%, 2/54), GHIN (18.18%, 12/66), and EGC (54.93%, 39/71) groups. The differences between any two groups were statistically significant (P < 0.05). Similarly, in the NIM group, cases with weakly positive expression of DNMT1 were predominant (91.11%, 82/90), and the rest were moderately positive cases (8.89%, 8/90). In the ILIN, IHIN, and ECRC groups, the rates of cases with weak or negative expression of DNMT1 were 46.30% (25/54), 12.68% (9/71), and 4.88% (4/82), respectively; with moderately positive expression were 53.70% (29/54), 71.83% (51/71), and 34.15% (28/82), respectively; and with strongly positive expression were 0.00% (0/54), 15.49% (11/71), and 60.98% (50/82), respectively. The differences between any two groups were also statistically significant (P < 0.05).CONCLUSIONThe overexpression of DNMT1 protein could effectively predict early GI cancers and severe precancerous lesions, which may have potential clinical application value.
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