Bone marrow-derived mesenchymal stem cells induced by inflammatory cytokines produce angiogenetic factors and promote prostate cancer growth

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.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3879-z) contains supplementary material, which is available to authorized users.

Use of Bone Marrow-Derived Mesenchymal Stem Cells in Prostate Cancer Could Increase the Risk of Cancer Progression

“…The study showed that BM-MSCs resulted in prostate cancer progression through cell fusion. Similar results were shown by the Yang et al [7] study wherein tumor necrosis factor-α and interferon-γ treated MSCs were shown to promote prostate tumor growth in a syngeneic mouse model. The prostate tumor and tumor stroma secreted transforming growth factor-β1 have shown to induce transdifferentiation of the BM-MSCs into cancer-associated fibroblast aiding in the progression of cancer [8,9].…”

Commitment to Aerobic Glycolysis Sustains Immunosuppression of Human Mesenchymal Stem Cells

“…IFN‐γ at concentrations from 5 ng/ml up to 100 ng/ml has been used to induce hMSC immune polarization with most of studies using IFN‐γ at concentrations between 20 ng/ml and 50 ng/ml . In addition to immune modulation, the influence of IFN‐γ on hMSC proliferation , trilineage differentiation , migration , transcriptome profile , and secretion of angiogenic and other tropic factors has been extensively reported.…”

Resveratrol improves human umbilical cord-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury

“…Furthermore, Malhotra et al 45 found that PDGF-C was a direct transcriptional target of Nrf2. In addition, BMMSCs stimulated by pro-inflammatory cytokines increased the expression of PDGF via the Nrf2-HIF-1α pathway and promoted prostate cancer growth 46 . Based on Figure S5 , we suggest that Res promote the PDGF-DD expression of hucMSCs possibly through regulating Nrf2.…”