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

Abstract

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 epithelium–derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture–conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer–focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays. Results ASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory 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.

Epigenome-wide DNA methylation profiling of periprostatic adipose tissue in prostate cancer patients with excess adiposity—a pilot study

“…Findings from other oncological models highlight excess adiposity-associated impact in methylation markers known to associate with potential effect in the cancer microenvironment (e.g., aromatase, prostaglandin E 2 receptor in breast cancer) [ 34 , 35 ]. Obesity has also been shown to associate with methylation of cancer-related genes (E-cadherin, p16, and RAR-β(2)) directly in malignant breast cells [ 36 , 37 ].…”

Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

“…The human prostate cancer cell line PC3 was obtained from American Type Culture Collection and maintained in 10% fetal bovine serum (FBS, Fisher) in Roswell Park Memorial Institute medium 1640 (RPMI, Corning). ASCs from two male Caucasian donors, generously provided by J. Gimble (Tulane University), were collected as previously described ( Zolochevska et al 2014 ) and cultured on fibronectin-coated plasticware in modified media conditions that have been described previously ( Ruiz et al 2010 ). ASCs from Donor 1 were isolated from midsection liposuction, and Donor 2 ASCs were isolated from liposuction samples from breast tissue.…”

“…It is thought that these cell types are recruited into tumors to promote healing and to potentially quell the inflammatory response ( Aggarwal and Pittenger 2005 ; González et al 2009 ). Although many investigators, including ourselves, are utilizing ASCs as a potential therapeutic modality because of their inherent tropism towards tumors ( Hall et al 2007 ; Zolochevska et al 2014 ), emerging evidence has suggested that endogenous ASCs may also play a critical role in tumor progression depending on the cellular context ( Barron and Rowley 2012 ; Kidd et al 2012 ). Moreover, the potential effects of environmental toxicants such as iAs on these endogenous cells is unknown.…”

The Comparison of Adipose Stem Cell and Placental Stem Cell in Secretion Characteristics and in Facial Antiaging

“…Mesenchymal stem cells are a type of adult stem cell with the attributes of self-renewing and multipotency. They can be used in biomedical research, new drug development, and toxicology studies, and so forth [ 1 ]. Currently this type of cell is a focal point in clinical research and application [ 2 – 4 ].…”