Mesenchymal stem cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model

Abstract

Lung cancer is a major public health problem in the western world, and gene therapy strategies to tackle this disease systemically are often impaired by inefficient delivery of the vector to the tumour tissue. Some of the main factors inhibiting systemic delivery are found in the blood stream in the form of red and white blood cells (WBCs) and serum components. Mesenchymal stem cells (MSCs) have been shown to home to tumour sites and could potentially act as a shield and vehicle for a tumouricidal gene therapy vector. Here, we describe the ability of an adenoviral vector expressing TRAIL (Ad.TR) to transduce MSCs and show the apoptosis-inducing activity of these TRAIL-carrying MSCs on A549 lung carcinoma cells. Intriguingly, using MSCs transduced with Ad.enhanced-green-fluorescent-protein (EGFP) we could show transfer of viral DNA to cocultured A549 cells resulting in transgenic protein production in these cells, which was not inhibited by exposure of MSCs to human serum containing high levels of adenovirus neutralizing antibodies. Furthermore, Ad.TR-transduced MSCs were shown not to induce T-cell proliferation, which may have resulted in cytotoxic T-cell-mediated apoptosis induction in the Ad.TR-transduced MSCs. Apoptosis was also induced in A549 cells by Ad.TR-transduced MSCs in the presence of physiological concentrations of WBC, erythrocytes and sera from human donors that inhibit or neutralize adenovirus alone. Moreover, we could show tumour growth reduction with TRAIL-loaded MSCs in an A549 xenograft mouse model. This is the first study that demonstrates the potential therapeutic utility of Ad.TR-transduced MSCs in cancer cells and the stability of this vector in the context of the blood environment.

Perspectives in Engineered Mesenchymal Stem/Stromal Cells Based Anti- Cancer Drug Delivery Systems

“…Contrary to previously said, MSCs (similar to most other healthy cells) are unsusceptible to TRAIL-induced apoptosis [71]. In addition to this, in the TRAIL transfected adult MSCs, fetal-MSCs and umbilical cord matrix stem cells, there are almost undetectable levels of apoptotic pathway components (caspase-8 and caspase-9) [110].…”

“…In experiments with MSCs expressing tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (a type II membrane ligand from Tumor Necrosis Factor (TNF) family) anticancer effects are also detected, probably by induction of apoptosis [68][69][70][71][72][73][74]. This effect was reported in case of prostate cancer investigated [19], and also in other experimental cancer models (glioma and lung cancer).…”

“…MSCs secreting TRAIL have been tested in different models of cancers in vivo, resulting in notable anti-tumor effects [19,68,71,72,88,109]. Contrary to previously said, MSCs (similar to most other healthy cells) are unsusceptible to TRAIL-induced apoptosis [71].…”

Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis

“…Most of previous published studies used the serotype 5 adenoviral vector (Ad5) as a delivery vector to deliver hTRAIL into the targeted cells [29][30][31][32][33][34][35] although other vector systems were also used, such as AAV. 36 Some studies used the E1 deleted Ad5 vector, which vector could not replicate in the targeted cells.…”

Therapeutic effect of suicide gene-transferred mesenchymal stem cells in a rat model of glioma

“…Studies have also shown the antiproliferative, antitumor and immunomodulatory effects of interferon-a, 27 a multifunctional regulatory cytokine. Mohr et al 28 reported the ability of an adenoviral vector expressing tumor necrosis factor-related apoptosis-inducing ligand to transduce MSCs and the subsequent therapeutic efficacy of these MSCs in a lung cancer model. The potential of mesenchymal progenitor cells to assist the delivery of an oncolytic virus, which targets virus-mediated lysis of tumor cells has been evaluated and may be a novel approach for human glioma therapy.…”