Abstract
Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAILDR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAILDR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments.
Highlights
STRAIL variants and 5-FU lead to tumor remission R Yu et al in vitro and in vivo.[10,11,12,13] in clinical trials with recombinant TRAIL protein and agonistic antibodies to TRAIL-R2, only moderate therapeutic activities have been found.[14]
For our combination treatment experiment, we chose concentrations of the two agents that gave rise to relatively low specific apoptosis levels and pretreated HCT116 cells with 10 mM 5-FU for 24 h followed by 1 ng/ml recombinant TRAIL (rTRAIL) for an additional 24 h before we measured cell death
It belongs to the family of drugs called antimetabolites and works through irreversible inhibition of thymidylate synthase. 5-FU has been shown to sensitize to TRAIL-induced apoptosis via various mechanisms including upregulation of TRAIL-R expression and/or downregulation of the anti-apoptotic protein cFlip.[26]
Summary
STRAIL variants and 5-FU lead to tumor remission R Yu et al in vitro and in vivo.[10,11,12,13] in clinical trials with recombinant TRAIL (rTRAIL) protein and agonistic antibodies to TRAIL-R2, only moderate therapeutic activities have been found.[14]. A further barrier for TRAIL therapies is that a substantial proportion of tumors are relatively resistant to the effects of TRAIL.[24] To this end, we could show that a sensitization approach with the commonly used anticancer compound 5fluorouracil (5-FU) in conjunction with systemically administered MSC.sTRAIL worked in vitro and in vivo. The effect was mediated by protein 53 (p53)-independent increases in the expression of TRAIL-R2, and MSCs secreting a TRAIL-R2-specific sTRAIL variant (MSC.sTRAILDR5) gave rise to significantly higher apoptosis than MSC.sTRAIL (wildtype sTRAIL) or MSC.sTRAILDR4 (TRAIL-R1-specific variant) in 5-FU-pretreated HCT116 cells. In a second sensitization approach, we targeted the antiapoptotic protein XIAP (Xlinked inhibitor of apoptosis protein) by RNA interference (RNAi) in TRAIL-resistant pancreatic carcinoma cells and could show that MSC.sTRAILDR4 exerted significantly increased apoptosis-inducing activity as compared with MSC.sTRAIL or MSC.sTRAILDR5. MSC-mediated delivery of optimized sTRAIL variants to tumors combined with conventional chemotherapy or inhibition of apoptosis resistance factors such as XIAP could become a novel, patient-tailored treatment strategy for various oncological diseases
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