Abstract
BackgroundProstate is susceptible to infection and pro-inflammatory agents in a man’s whole life. Chronic inflammation might play important roles in the development and progression of prostate cancer. Mesenchymal stem cells (MSCs) are often recruited to the tumor microenvironment due to local inflammation. We have asked whether stimulation of MSCs by pro-inflammatory cytokines could promote prostate tumor growth. The current study investigated the possible involvement of MSCs stimulated by pro-inflammatory cytokines in promotion and angiogenesis of prostate cancer through relative pathway in vitro and in vivo.MethodsA syngeneic mouse model of C57 was established. The murine prostate cancer cells (RM-1) mixing with MSCs treated with tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) or vehicle were subcutaneously injected into C57 mice. Tumor volume of C57 mouse model was estimated and serum level of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) was test by Enzyme-linked Immunosorbent Assay (ELISA). A hen egg test-chorioallantoic membrane (HET-CAM) assay was applied to test the effect of conditioned media of stimulated MSCs in chorioallantoic membrane angiogenesis. Short interfering RNA (siRNA) knocked down either hypoxia-inducible factor-1alpha (HIF-1α) or nuclear factor-erythroid-2-related factor 2 (NRF2) were employed. mRNA of PDGF and VEGF in MSCs, as well as NRF2 and HIF-1α was test by Real time polymerase chain reaction (PCR) analyses. Protein expression levels of PDGF and VEGF from conditioned medium, NRF2, HIF-1α, as well as PDGF and VEGF in MSCs were detected by Western blot analysis.ResultsMSCs treated with TNF-α and IFN-γ promote tumor growth in C57 syngeneic mouse model, correlating with increased serum level of PDGF, VEGF. HET-CAM assay shows the angiogenic effect of conditioned medium of MSCs pre-treated with the pro-inflammatory cytokines. mRNA and protein levels of two pro-angiogenic factors (PDGF and VEGF) and key hypoxia regulators (HIF-1α and NRF2) in MSCs were induced after MSCs’ pretreatment. siRNA knockdown either HIF-1α or NRF2 results reduction of PDGF and VEGF expression.ConclusionsMSCs stimulated by pro-inflammatory cytokines increase the expression of PDGF and VEGF via the NRF2-HIF-1α pathway and accelerate prostate cancer growth in mice.
Highlights
Prostate is susceptible to infection and pro-inflammatory agents in a man’s whole life
RM-1 cells mixing Mesenchymal stem cells (MSC) treated with TNF-α and Interferon gamma (IFN-γ) for 12 h were co-injected C57 mice; RM-1 cells mixing with the MSCs treated with vehicle for 12 h was as the control group
The results show that MSCs treated with TNF-α and IFN-γ promote the yielding of serum vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) and accelerate growth of RM-1 prostate tumors in vivo
Summary
Prostate is susceptible to infection and pro-inflammatory agents in a man’s whole life. Chronic inflammation might play important roles in the development and progression of prostate cancer. We have asked whether stimulation of MSCs by pro-inflammatory cytokines could promote prostate tumor growth. Growing evidence suggests that chronic inflammation might play important roles in the development and progression of PCa [2]. Tumor stroma include cancer-associated fibroblasts, bone marrow-derived mesenchymal stem cells (BM-MSCs), smooth muscle cells, and various inflammatory cells such as lymphocytes, endothelial cells, macrophages [5]. These cells, as a whole, are known as tumor microenvironment, which has profound impact on cancer progression. Several proinflammatory cytokines, including interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and interleukin-10 (IL-10), have been shown to contribute to both the initiation and development of cancer [9,10,11]
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