Mesenchymalstem Cells Modified With Sirt1 Induces Immunopotentiation To Suppress Prostate Cancer Tumor Growth

Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells, which can be isolated from bone marrow and may differentiate intovarious specialized cell types under certain physiological or experimental conditions. Theimmunosuppressive function of MSCs being used inimmune disorder disease therapy has been well-demonstrated in several studies. MSCs are also applied as drug carriers for tumor therapy because of their migration ability to tumor tissue. However, due to the immunosuppressive function of MSCs, the application of MSCs in prostate cancer (PCa) therapy remains limited.In view of the limitation of MSCs in cancer therapy, it is necessary to investigate a new manner to make MSCs come into play effectively.Sirtuins is a molecular family with seven members (Sirt 1-7),of which Sirtl is the closest mammalian homologue of the yeast enzyme Sir2, a protein with an established capacity to influence yeast replicative lifespan. Consequently, the tremendous interest in Sirtl occured rapidly due to its possible role in eukaryote.It has been proved that Sirtl plays an important role in regulating several biological functions, such as aging, metabolism, DNA damage and tumor development in mammalian. Dramatically, evidence suggested that Sirt1 expression is upregulated significantly in prostate cancer. But little is known at present about the metergasis of MSCs when Sirtl overexpression was performed.In this study, we demonstrated the function change of MSCs when infected with an adenovirus containing the Sirtl gene in PCa tumor growth by using mouse PCa cell line RM-1 and investigated the underlying mechanism. Firstly,we observed the metergasis of MSCs derived from bone marrow when they are infected with the Sirtl overexpression (MSCs-Sirtl) on RM-1 cells growth in vivo. We found that the tumor volume increased at an accelerated rate. The development of RM-1 cells coinjected with MSCs was significantly faster than those injected alone, while RM-1 cells coinjected with MSCs-Sirtl grew the most slowly. Besides that, compared with the group injected with RM-1 cells alone, the weight of tumor obviously increased in the group coinjected with MSCs and RM-1 cells. However, when RM-1 cells were coinjected with MSCs-Sirtl, the weight of tumor showed a significant reduction. Interestingly,MSCs-Sirtl treatment groups had higher IFN-y levels in mice serum than those with other treatment groups. So we speculated that the inhibition effect of MSC-Sirtl on PCa cells growth may be related to the immunopotentiation in vivo. Furthermore, dramatically higher numbers of IFN-y-secreting NK cells were detected in the mice tumor xenograft tissues of MSCs-Sirtl group than those the mice tumor xenograft tissues of control group, as well as MSCs-GFP group. Besides that, we isolated splenocytes from the mice after sacrifice to detect the cytolytic NK activity. The data showed that there was an significant enhancement of cytolytic NK activity in MSCs-Sirtl treatment groups compared with those with other treatment groups. The impulsive effect of MSCs-Sirtl on RM-1 cells in vivo could be reversed by inhibition of IFN-y and NK cells.Besides that, CXC motif chemokine 10 (CXCL10) showed the high level expression in MSCs-Sirtl treatment group in vivo and in vitro. We also proved that CXCL10 was the key chemotactic factor that recruited natural killer cells for MSCs-Sirtl-induced antitumor effect through CXCL10 neutralization.At present, we infected MSCs with an adenovirus containing the Sirtl gene and demonstrated the antitumor founction of them through enhancing local inflammatory microenvironment mediated by NK cells. Overall, our results conclude that MSCs infected with the Sirtl overexpression may be elicited the collection of NK cells in tumor inflammatory microenvironment, which will help inhibit PCa tumor growth effectively. Significantly, our preliminary results suggest that MSCs-Sirtl may represent a promising strategy for tumor treatment.That is to say, this modification to MSCs would be considered as a potential therapeutic option to treat patient in clinical application.