Abstract
Mesenchymal stem cells (MSCs) are generally used in regenerative medicine, tissue engineering and therapy for immune disorder diseases. However, due to the immunosuppressive function of MSCs, the application of MSCs in breast cancer therapy remains limited. Sirt1 is the closest mammalian homologue of the yeast enzyme Sir2 which has an established capacity to influence yeast replicative lifespan. In this study, we demonstrated the effect of MSCs with Sirt1 overexpression (MSCs-Sirt1) in mice bearing 4T1 breast cancer and investigated the underlying mechanism. Firstly, we found that MSCs could accelerate breast tumor growth with promoted proliferation and inhibited apoptosis, whereas MSCs-Sirt1 significantly suppressed tumor growth with proliferation inhibition and apoptosis promotion. Moreover, we detected that NK cells were the prominent antitumor effectors for the MSCs-Sirt1-induced antitumor activity. Besides that, CXCL10 and IFN-γ showed the high level expression in MSCs-Sirt1 treatment group. The impulsive effect of MSCs-Sirt1 on 4T1 cells in vivo could be reversed by inhibition of CXCL10 and IFN-γ. Overall, our results suggest that MSCs-Sirt1 can effectively inhibit breast tumor growth via the recruitment of NK cells in tumor inflammatory microenvironment.
Highlights
Promote the survival of damaged cells[13,14,15]
When 4T1 cells were coinjected with MSCs-Sirt[1], tumor showed a significant reduction in weight (Fig. 1B,C)
The data indicate that the effect of MSCs-Sirt[1] in tumor suppression can be greatly blocked by CXCL10 inhibition. These results demonstrate that CXCL10 can recruit Natural killer (NK) cells contributing to the MSCs-Sirt[1] induced suppression of breast tumor growth in mice
Summary
Promote the survival of damaged cells[13,14,15]. MSCs from bone marrow have been shown to be an important component of the tumor microenvironment, assisting tumor escape from immunosurveillance[16], which contributes to the growth of cancer cells. It has been proved that Sirt[1] plays an important role in regulating several biological functions, such as aging, metabolism, DNA damage and tumor development in mammalian[20]. It has been reported that overexpression of SIRT1 in aged MSCs could reverse the senescence phenotype and stimulated cell proliferation. The exactly effect of mammalian Sirt[1] overexpressed MSCs on cancer as a metabolic and age-related disease remain unclear. We constructed Sirt[1] overexpressed MSCs (MSC-Sirt1) through infecting MSCs with an adenovirus containing the Sirt[1] gene and used the 4T1 breast cancer cell line to observe the potential effect of MSC-Sirt[1] on regulating breast cancer cells growth in vivo. This report shows that MSCs-Sirt[1] can exert a profound inhibitory effect on tumor growth and this would be a new potential manner for breast cancer therapy
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