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. 2016 Oct;25(20):1513-1531.
doi: 10.1089/scd.2016.0120. Epub 2016 Sep 7.

Engineered Mesenchymal Stem Cells as an Anti-Cancer Trojan Horse

Adam Nowakowski  1 , Katarzyna Drela  1 , Justyna Rozycka  1 , Miroslaw Janowski  1   2 , Barbara Lukomska  1
Affiliations

Engineered Mesenchymal Stem Cells as an Anti-Cancer Trojan Horse

Adam Nowakowski et al. Stem Cells Dev. 2016 Oct.

Abstract

Cell-based gene therapy holds a great promise for the treatment of human malignancy. Among different cells, mesenchymal stem cells (MSCs) are emerging as valuable anti-cancer agents that have the potential to be used to treat a number of different cancer types. They have inherent migratory properties, which allow them to serve as vehicles for delivering effective therapy to isolated tumors and metastases. MSCs have been engineered to express anti-proliferative, pro-apoptotic, and anti-angiogenic agents that specifically target different cancers. Another field of interest is to modify MSCs with the cytokines that activate pro-tumorigenic immunity or to use them as carriers for the traditional chemical compounds that possess the properties of anti-cancer drugs. Although there is still controversy about the exact function of MSCs in the tumor settings, the encouraging results from the preclinical studies of MSC-based gene therapy for a large number of tumors support the initiation of clinical trials.

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Conflict of interest statement

Author Disclosure Statement All authors declare that no competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
Complex interaction between MSCs and cancer cells. (A) Naïve MSCs may act through various pathways to induce tumor inhibition. PTEN–phosphatase and tensin homolog deleted on chromosome 10 protein, TIMP-1/-2, TRAIL. (B) MSCs possess natural ability to migrate toward the tumor and recruit to the tumor cell mass, contributing to the tumor progression by the decrease of apoptosis rate and anti-tumor immune response; besides, MSCs elicit anti-cancer drug resistance and stimulate metastasis. (C) Spontaneous MSC tumor transformation is also one of the possible ways of MSC biological activities. MSCs, mesenchymal stem cells; TIMP-1/-2, tissue inhibitor of metalloproteinase-1 and -2; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.
<b>FIG. 2.</b>
FIG. 2.
Suicide gene delivery system mediated by MSCs. (A) The hsv-tk gene is one of the suicide genes employed in MSC-based anti-tumor studies. Nontoxic pro-drug GCV is converted into toxic compound GCV-triphosphate (GCV-ppp) due to HSV-TK activity in HSV-TK-producing MSCs. GCV-ppp is then delivered to the target tumor cells through the gap-junctional system, and it is subsequently incorporated into cell metabolic pathways, causing eventual cell death. (B) CD also found its application in MSC-based studies. MSCs modified do produce a CD carry-out enzymatic reaction of nontoxic pro-drug 5-FC to produce the toxic product 5-FU, which is secreted and reaches target tumor cells, eliciting tumor cell death. (C) iCas-9 system. Inducible caspase-9 system is based on the pro-apoptotic activity of the caspase-9 delivered to the target tumor cell by adenoviral transfection. First, MSCs are genetically engineered to produce an invasive form of adenoviral construct containing the icas-9 gene. After target tumor cell delivery, iCas-9 protein is effectively produced followed by the small-molecule CID stimulation, which triggers iCas-9 dimerization and apoptosis pathway induction. 5-FC, 5-fluorocytosine; 5-fluorouracil; CD, cytosine deaminase; CID, chemical inducer of dimerization; GCV, Ganciclovir; HSV-TK, herpes simplex virus-thymidine kinase.
<b>FIG. 3.</b>
FIG. 3.
Diversity of anti-tumor MSC-based approaches. (A) Several anti-tumor angiogenesis approaches could be appreciated. Some of them target the VEGF–VEGF–R axis, with the examples of soluble vascular endothelial growth factor receptor-1 (sFlt-1) or PEDF. Others recruit Thrombospondin 1 (TSP-1) or interferon-inducible protein-10 (IP-10), both of which are stated anti-angiogenic factors. (B) Various cytokines found their application in anti-tumor studies: interferons (IFNs), tumor necrosis factor super family proteins (TNFs), and interleukins (ILs). TRAIL, LIGHT, homologous to Lymphotoxin, exhibits inducible expression and competes with HSV Glycoprotein D for binding to Herpesvirus entry mediator, a receptor expressed on T lymphocytes. (C) A plethora of miRNAs found their application in MSC-based studies on tumor cell progression. After target tumor cell delivery, miRNAs might contribute to the decrease in tumor angiogenesis, viability and growth, invasion and migration. Furthermore, miRNAs might cause chemosenzitization of tumor cells for anti-tumor drugs. Additionally, synthetic small interfering miRNAs (siRNA) might be also employed as in the case of IL-6 production silencing. (D) MSCs could be used as vehicles for regular chemical anti-cancer acting compounds, that is, PTX, DOX, or GCB. DOX, Doxorubicin; GCB, Gemcitabine; PTX, Paclitaxel; PEDF, pigment epithelium-derived factor; VEGF, vascular endothelial growth factor; VEGF-R, VEGF–Receptor.
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