Human adipose-derived mesenchymal stromal cell pigment epitheliumederived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells

摘要

Background aims. Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells. Methods. ASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epitheliumederived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC cultureeconditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancerefocused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays. Results. ASCs transduced with lentiviral vectors were able to mediate expression of several tumorinhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs. Conclusions. These results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects.