Intrinsic properties of tumour cells have a key impact on the bystander effect mediated by genetically engineered mesenchymal stromal cells

Matúšková, Miroslava; Baranovičová, Lenka; Kozovská, Zuzana; Durinikova, Erika; Pastorakova, Andrea; Hunáková, Ľuba; Waczulı́ková, Iveta; Nencka, Radim; Kučerová, Lucia

doi:10.1002/jgm.2684

Cited by 28 publications

(39 citation statements)

References 37 publications

(65 reference statements)

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“…18,22,28 In order to confirm the extent of a bystander effect, relative cell fluorescence was measured on EGFP-A375 cells treated with the CD-MSC/5FC regimen in vitro. 29 The tumor cell fluorescence significantly decreased already 48 h after the treatment start (Figure 1a), and within 5 days 499% of tumor cells were eradicated (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

“…17 The combination of a cytosine deaminase with a prodrug 5-fluorocytosine (5FC) is beneficial in the tumor cells expressing key molecular determinants of the sensitivity. 18 5FC is clinically approved antimycotic non-toxic drug that can be converted to a potent chemotherapeutic 5-fluorouracil (5FU) and its metabolites by non-mammalian enzymes. Nucleotide analogs of 5FU readily incorporate into the RNA and DNA by intracellular enzymes leading to high cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

et al. 2014

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Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

et al. 2014

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“…These melanoma cells express high levels of thymidylate synthase and thymidine phosphorylase (enzymes of the nucleotide mechanism) which significantly contribute to the incorporation of the 5FC-metabolites into DNA and RNA thus efficiently mediating the cytotoxicity [11]. Our data also indicated that low expression levels of multidrug resistance gene(s) MRP5 (ABCC5) and MRP8 (ABCC11) might contribute to A375 cell sensitivity to the CD-MSC/5FC combination.…”

mentioning

confidence: 66%

“…Thus the cytotoxicity and antitumor action is targeted to the site of the tumor growth and temporally limited by the inherent suicide gene function [9; 10]. However, these approaches have their limitations and we have identified several biomarkers in the tumor cells which contribute to the efficiency of the treatment regimen [11].…”

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confidence: 99%

3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Bohovic¹,

Demkova²,

Cihova³

et al. 2015

neo

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Mesenchymal stromal cells (MSC) exhibit beneficial properties to serve as cellular vehicles for enzyme/prodrug cancer gene therapy approaches. We have previously shown that engineered human adipose tissue-derived MSC in combination with non-toxic prodrug mediated substantial cytotoxic and antitumor effect. The aim of this study was to develop advanced 3D cultivation method to serve for modelling of the therapeutic outcome in vitro. We have used engineered MSC expressing fusion transgene cytosine deaminase::uracilphosphoribosyltransferase (CD-MSC) in combination with prodrug 5-fluorocytosine (5FC). This therapeutic regimen designated CD-MSC/5FC was combined with the human melanoma cells A375 or EGFP-A375 in both standard monolayer culture and 3-dimensional (3D) multicellular nodules. The extent of cytotoxicity was evaluated by standard viability assay MTS, ATP-based luminescence assay, fluorimetric test, measurement of Caspase-3/7 activation and DNA laddering. The data have shown that the extent of cytotoxic bystander effect mediated by CD-MSC/5FC is significantly lower in 3D culture conditions. However, these data better recapitulate the therapeutic efficiency as observed previously in vivo. We suggest here to use the 3D multicellular culture conditions for better prediction of the therapeutic outcome in mouse xenograft models.

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“…We observed low effi cacy of HSVtk-MSC/GCV approach on tumour cell lines defi cient in GJIC. The expression level of enzymes involved in nucleotide metabolism is very important for treatment effi cacy as well as expression of ABC transporters which are responsible for effl ux of chemotherapeutics from tumour cells into extracellular space (20).…”

Section: Gene Therapy Mediated By Mesenchymal Stromal Cellsmentioning

confidence: 99%

Genetically engineered mesenchymal stromal cells in cancer gene therapy

Matúšková¹,

Durinikova²,

Altaner³

et al. 2018

BLL

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Based on our experimental data, we aimed to emphasise the perspectives of the use of mesenchymal stromal cells (MSC) in the cancer gene therapy. On the other hand, we would like to point out factors which should be taken into consideration at their clinical use. In this review we defi ne MSC as unique targets for targeted therapy. We proved the effi cacy of experimental therapeutic approach utilising enzymatic conversion of non-toxic prodrug into chemotherapeutic by engineered MSC, and we observed signifi cant cytotoxic effect in many preclinical models including metastatic disease. Treatment was enabled by affi nity of MSC to tumour tissue and subsequent delivery of therapeutic molecule into the tumour. We also observed decreased effi cacy of cell-mediated gene therapy on chemoresistant tumour cells. Moreover MSC can exert a supportive effect on tumour cells as well as to decrease the effi cacy of conventional treatment. Besides obvious unique benefi ts connected to the use of MSC we pointed also to possible risks associated with their clinical application (Ref. 24). Text in PDF www.elis.sk.

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Intrinsic properties of tumour cells have a key impact on the bystander effect mediated by genetically engineered mesenchymal stromal cells

Abstract: GJIC, expression of enzymes involved in drug metabolism and ABC transporters correlate with the response of tumour cells to treatment by MSC-expressing prodrug-converting genes.

Cited by 28 publications

References 37 publications

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Genetically engineered mesenchymal stromal cells in cancer gene therapy

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