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PhiC31/PiggyBac modified stromal stem cells: effect of interferon ? and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma.

ABSTRACT: TRAIL and IFN? are promising anti-cancer cytokines and it has been shown that IFN? may sensitize cancer cells to TRAIL. Adipose derived mesenchymal stem cells (ADSCs) are attractive vehicles for delivering anti-cancer agents. In this study, we evaluated the therapeutic potential of PhiC31 (?C31) recombinase and/or piggyBac transposase (pBt) modified ADSCs expressing either TRAIL, IFN?, or co-expressing TRAIL/IFN? in mouse models of melanoma.The expression and bioactivity of mouse IFN? and TRAIL in ?C31 and pBt modified cells were confirmed. We examined the effects of modified ADSCs on signal intensity of red fluorescence protein expressed by melanoma cells in subcutaneous tumors or established lung metastases and on survival (6 mice per group). We also conducted a flow cytometric analysis of systemic CD4(+)CD25(+)FOXP3(+) T regulatory cells (Tregs) and histological analysis of melanoma tumors. Data were analyzed by Student t test, ANOVA, and log-rank tests. All statistical tests were two-sided.We demonstrated non-viral DNA-integrating vectors can be used for stable transgene expression. IFN? inhibited melanoma cell growth in vitro probably via IFN?-induced JAK/STAT1 signaling pathway activation. Murine TRAIL induced apoptosis in the human cell lines CAOV-4 and Ej-138, while MCF7 and B16F10 cells appeared to be insensitive to TRAIL. Treatment of melanoma cells with IFN? did not influence their response to TRAIL. In contrast, results from in vivo studies showed that IFN?-expressing ADSCs, engrafted into tumor stroma, inhibited tumor growth and angiogenesis, prevented systemic increase of Tregs, increased PD-L1 expression and CD8+ infiltration (but not interleukin-2+ cells), and prolonged the survival of mice (68 days, 95% confidence interval [CI] = 52 to 86 days compared to 36 days, 95% CI = 29 to 39 days for control, P

SUBMITTER: Bahrambeigi V

PROVIDER: S-EPMC4258801 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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PhiC31/PiggyBac modified stromal stem cells: effect of interferon γ and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma.

Bahrambeigi Vahid V Ahmadi Nafiseh N Moisyadi Stefan S Urschitz Johann J Salehi Rasoul R Haghjooy Javanmard Shaghayegh S

Molecular cancer 20141126

<h4>Background</h4>TRAIL and IFNγ are promising anti-cancer cytokines and it has been shown that IFNγ may sensitize cancer cells to TRAIL. Adipose derived mesenchymal stem cells (ADSCs) are attractive vehicles for delivering anti-cancer agents. In this study, we evaluated the therapeutic potential of PhiC31 (φC31) recombinase and/or piggyBac transposase (pBt) modified ADSCs expressing either TRAIL, IFNγ, or co-expressing TRAIL/IFNγ in mouse models of melanoma.<h4>Methods</h4>The expression and b ...[more]

PMID: 25428727

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Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other âdeath receptorâ ligands may explain not only the inability of TRAIL and TRAIL âdeath receptorâ agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell â mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). We showed that acquired TRAIL resistance was associated with complex disruption of both extrinsic and intrinsic apoptotic pathways manifested by acquired multi-drug resistant phenotype of TR1, TR2, and TR3 clones. To identify changes associated with TRAIL resistance of Jurkat cells we performed genome-wide gene expression analysis of TRAIL-resistant clones (TR) and compared to WT Jurkat cells. We identified significantly increased expression (1.33-fold change with adjusted p < 0.05) of 73 genes in TR1 clone, 53 genes in TR2 clone and 8 genes in TR3 clone, and significant decrease in expression (0.75-fold change with adjusted p < 0.05) of 174 genes in TR1 clone, 36 genes in TR2 clone and 28 genes in TR3 clone. There was an overlap of only 2 significantly overexpressed (midkine / MDK and zinc finger and BTB domain containing 16 gene / ZBTB16 / PLZF) and 4 downregulated genes (YAP1, IGJ, EIF1AY, RPS4Y1) in all three TR clones. Total cellular RNA was isolated from biologic duplicates of untreated Jurkat cells (WT) and TRAIL resistant Jurkat cell line subclones (TR1, TR2, TR3) established by selective pressure of TRAIL 1000 ng/mL on Jurkat cells over the period of 12 weeks.

Dataset Information

PhiC31/PiggyBac modified stromal stem cells: effect of interferon ? and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma.

Publications

PhiC31/PiggyBac modified stromal stem cells: effect of interferon γ and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma.

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