Study of interactions between between tumour cells and mesenchymal stem cells carrying suicide genes

We compared the efficacy of the most frequently used systems, and evaluated the extent of a bystander effect mediated by therapeutic MSC towards cell lines derived from different tumours. Two approaches were examined: (i) herpes simplex virus thymidine kinase (TK)/ganciclovir (GCV) and (ii) yeast cytosine deaminase fused with uracil phosphoribosyltransferase (CD::UPRT)/5-fluorocytosine (5-FC). We demonstrated various response to the treatment. Both systems were effective only on glioblastoma cells 8-MG-BA. The CD::UPRT-MSC/5-FC system showed efficiency on melanoma A375 cells. We decreased the sensitivity of 8-MG-BA cells and A375 cells to the CD::UPRTMSC/ 5-FC system by pharmacological inhibition of thymidylate synthase, and we achieved a similar result in A375 cells by inhibition of thymidine phosphorylase. lthough we demonstrated functional GJIC in A375 cells, TK-MSC were ineffective in mediating the bystander effect similarly to HeLa cells, which were also relatively resistant to CD::UPRT-MSC/5-FC treatment. TK-MSC/GCV treatment had a strong cytotoxic effect on MDA-MB-231 cells derived from breast carcinoma, whereas CD::UPRT-MSC/5-FC treatment failed as a result of overexpression of the gene for ABCC11. Transfection of the MDA-MB-231 cell line with small interference RNA specific to ABCC11 led to a significantly increased sensitivity to the CD::UPRT-MSC/5-FC approach. In summary, gap junctions, expression of enzymes involved in drug metabolism and ABC transporters correlate with the response of tumour cells to treatment by genetically engineered MSC. Intrinsic properties of tumour cells have key impact on the bystander effect mediated by genetically engineered MSC. Matuskova M, Baranovicova L, Kozovska Z, Durinikova E, Pastorakova A, Hunakova L, Waczulikova I, Nencka R, Kucerova L.J Gen Med. 2012 Dec 21;14:776-87. doi: 10.1002/jgm2684