Our study revealed that an increased number of MCs in GC patients is correlated with a higher frequency of Foxp3 expression. Numerous studies have documented an increased level of Foxp3 during GC progression (14
). However, the role of MCs in GC remains unclear.
Ribatti et al
) demonstrated that MC density correlates with progression of patients with gastric carcinoma. This means that the density of MCs is positively correlated with the development of the disease from stage I to stage IV. However, there have been reports of a protective role for MCs in human cancer. For instance, in a multivariate analysis of colorectal cancer patients, high counts of eosinophils and MCs predicted longer survival (17
). MC tryptases activate the nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ); the expression of PPAR-γ is associated with improved clinical outcome in colon cancer (18
). Our findings imply a complex correlation between the increased number of infiltrating MCs and advanced stages of GC patients.
These results suggest that higher numbers of MCs are associated with poor outcomes, which is similar to the results of previous studies reported in GC and other tumors (19
). The present study not only provides support for the correlation between MCs and the stages of GC, but also focused on mechanisms other than angiogenesis, which has already been demonstrated (16
). We studied the correlation between Tregs and MCs in order to provide an explanation of the influence of MCs on the stage of GC. Several studies have researched the immune suppression mechanism of MCs in tumors (11
). However, to date, no study has directly demonstrated the correlation between the increased frequency of MCs and higher levels of Foxp3 in human GC. Our data demonstrate that MCs may affect the progression of GC, partially via interaction with Tregs. Studies in liver cancer reported similar results (32
). Numerous researchers consider IL-9 to be critical factor in this interaction (24
In several types of cancer, an increased level of Foxp3+
Tregs has been detected in tumor tissues and peripheral blood, consistent with their presumed function in immuno-suppression (27
). Much concern has also been attached to the roles of Foxp3 in human GC. There is a link between the concentration of Tregs and patient survival in GC (29
). Recently, a study partly explained the mechanisms of the weakened immune reactions in GC based on the overexpression of Foxp3 (31
). Yuan et al
) demonstrated a mechanism by which tumor-infiltrating Tregs with increased Foxp3 expression mediate immune suppression via COX-2/PGE2 production in the GC microenvironment. Furthermore, Tregs with higher levels of Foxp3 were able to suppress the proliferation of autologous CD4+
T cells. The suppression of the effector T-cell response was reversed by COX inhibitors and PGE2 receptor-specific antagonists. In 2011, Yuan et al
) performed further research on Tregs in GC and found that GC cells induce the development of Tregs via the production of TGF-β, by which the existence of cross-talk between the tumor and immune cells may regulate antitumor immune responses. Our research first confirmed that the expression of Foxp3 in tumor-infiltrating T lymphocytes was higher in the GC tissues compared with normal tissues. We also identified links between MCs and Foxp3, providing a new strategy of targeting Tregs and Foxp3. As mentioned, GC cells induce human CD4+
Tregs through the production of TGF-β (34
), and as MCs secrete TGF-β, we speculate that one of the ways in which MCs affect Tregs is their secretion of TGF-β, thus explaining the correlation between MCs and Foxp3 at the molecular level, and providing a new support and research direction for the immunosuppressive effects of MCs.
In conclusion, our results reveal that the frequency of MCs and the level of Foxp3 are increased in tumors compared with normal tissues. The significant correlation between MCs and Foxp3 may be considered to support the hypothesis that MCs play a role in immunosuppression in GC and may be, at least partially, responsible for their prognosis. These results are significant and may provide promising clinical treatments for cancer, in at least in three aspects. First, these findings show the significance of MCs in GC and provide a probable mechanism by which MCs affect GC development, thus providing references for the application of MC-regulating drugs. Second, there are few studies concerning the correlation between MCs and Foxp3 and the present study linked them and provided new insights into the mechanism of immune suppression. Third, we confirmed the close correlation between MCs and Tregs, making a foundation for the further study of the detailed mechanisms. Therefore, further studies should be performed to explore the mechanism of the correlation between MCs, Foxp3 and GC.