Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

Abstract

Disseminating tumors are one of the gravest medical problems. Here, we combine the tumor-specific apoptosis-inducing activity of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) with the ability of mesenchymal stem cells (MSCs) to infiltrate both tumor and lymphatic tissues to target primary tumors as well as disseminated cancer cells in a human pancreatic cancer mouse model. Furthermore, we targeted X-linked inhibitor of apoptosis protein (XIAP) by RNA interference (RNAi) inside the cancer cells to make use of the apoptosis sensitization as well the antimetastatic effect that is afforded by XIAP silencing. We generated MSCs, termed MSC.sTRAIL, that express and secrete a trimeric form of soluble TRAIL (sTRAIL). MSC.sTRAIL triggered limited apoptosis in human pancreatic carcinoma cells that were resistant to soluble recombinant TRAIL, which is most likely due to the enhanced effect of the direct, cell-mediated delivery of trimeric TRAIL. MSC.sTRAIL-mediated cell death was markedly increased by concomitant knockdown of XIAP by RNAi in the cancer cells. These findings were confirmed in xenograft models, in which tumors from the parental pancreatic carcinoma cells showed only growth retardation on treatment with MSC.sTRAIL, whereas tumors with silenced XIAP that were treated with MSC.sTRAIL went into remission. Moreover, animals with XIAP-negative xenografts treated with MSC.sTRAIL were almost free of lung metastasis, whereas animals treated with control MSCs showed substantial metastatic growth in the lungs. In summary, this is the first demonstration that a combined approach using systemic MSC-mediated delivery of sTRAIL together with XIAP inhibition suppresses metastatic growth of pancreatic carcinoma.

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

“…23 MSCs expressing and secreting tumor necrosis factor-related apoptosis-inducing ligand using systemic MSC-mediated delivery were shown to suppress metastatic growth of pancreatic carcinoma. 24 Furthermore, Toro et al have shown an efficient treatment of the metastatic dissemination of the ovarian tumor by yCD-UPRT gene-modified AT-MSCs in nude mouse model. 25 The authors did not consider existence of MSC-exosomes with suicide gene mRNA; therefore, the explanation was linked to the bystander effect.…”

TRAIL-engineered pancreas-derived mesenchymal stem cells: characterization and cytotoxic effects on pancreatic cancer cells

“…32,33 Increased number of MSC-mediated anticancer studies have shown MSCs to be an effective therapeutic tool and gene carrier for the treatment of pancreatic cancer. 34 To use MSCs as effective anticancer agent vehicles, we need a viable and practical source of MSCs and a method to successfully transfect MSCs with anticancer genes. To this end, we have successfully isolated and characterized MSCs from the ductal tissue of human donor pancreases and as well as, we have successfully transfected and expressed TRAIL in MSCs.…”

Genetically Engineered Mesenchymal Stem Cells

“…We have also designed additional supplementary treatments, like microRNA-21 (miR-21) inhibitors [139] and novel PI3-kinase/mTOR inhibitor, PI-103 [140] to augment the antitumor effect of different stem cell-mediated S-TRAIL therapy in vivo. A similar study has demonstrated that the combined approach using systemic MSC-mediated delivery of TRAIL together with XIAP inhibition suppresses metastatic growth of pancreatic carcinomas [141]. These findings offer a preclinical rationale for application of mechanism-based systemically delivered anti-proliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant tumors.…”