Abstract
The lysyl deacetylase SIRT1 acts as a metabolic sensor in adjusting metabolic imbalance. To explore the role of SIRT1 in tumor-stroma interplay, we designed an in vivo tumor model using SIRT1-transgenic mice. B16F10 mouse melanoma grew more quickly in SIRT1-transgenic mice than in wild-type mice, whereas SIRT1-overexpressing one grew slowly in both mice. Of human tumors, SIRT1 expression in stromal fibroblasts was found to correlate with poor prognosis in ovarian cancer. B16F10 and human ovarian cancer (SKOV3 and SNU840) cells were more proliferative in co-culture with SIRT1-overexpressiong fibroblasts. In contrast, SIRT1 within cancer cells has a negative effect on cell proliferation. In conditioned media from SIRT1-overexpressing fibroblasts, matrix metalloproteinase-3 (MMP3) was identified in cytokine arrays to be secreted from fibroblasts SIRT1-dependently. Fibroblast-derived MMP3 stimulated cancer cell proliferation, and such a role of MMP3 was also demonstrated in cancer/fibroblast co-grafts. In conclusion, SIRT1 plays differential roles in cancer and stromal cells. SIRT1 in stromal cells promotes cancer growth by producing MMP3, whereas SIRT1 in cancer cells inhibits growth via an intracellular event. The present study provides a basis for setting new anticancer strategies targeting SIRT1.
Highlights
Cancer cells live and act in conjunction with stromal cells residing in the vicinity of tumors or immigrating from bone marrow [1, 2]
Control and SIRT1-overexpressing B16F10 stable cell lines were grafted into wild type (WT) or SIRT1transgenic (TG) mice (Figure 1A)
These results suggest that SIRT1 in host stromal cells provides a tumorfavorable environment, whereas SIRT1 in cancer cells has a negative effect on tumor growth
Summary
Cancer cells live and act in conjunction with stromal cells residing in the vicinity of tumors or immigrating from bone marrow [1, 2]. Cancer-associated fibroblasts (CAFs), which are the most populous stromal cells, are not innocent neighbors but rather active assistants for cancer [3, 4]. Cancer cells and CAFs secrete many cytokines that stimulate the cooperative growth and activation among them [5]. SIRT1determines gene expression by deacetylating either histones or transcription factors [7, 8]. SIRT1 suppresses tumor formation and growth by preventing genotoxic stress and inducing apoptosis [11, 12]. It promotes tumor growth by inhibiting p53 and Foxo3a, and facilitates tumor expansion by inducing epithelial-to-mesenchymal transition [13,14,15]
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