Genetically engineered mesenchymal stromal cells producing TNFα have tumour suppressing effect on human melanoma xenograft.

BackgroundMesenchymal stromal cells (MSC) are a promising tool for targeted cancer therapy due to their tumour-homing ability. Intrinsic resistance enables the MSC to longer tolerate therapeutic factors, such as prodrug converting enzymes, cytokines and pro-apoptotic proteins. Tumour necrosis factor alpha (TNF) is known to be cytotoxic to a variety of cancer cells and exert a tumour-destructive capacity. MethodsMSC were retrovirally transduced to stable express an exogenous gene encoding the desired therapeutic agent hTNF. The effect of a TNF-producing adipose tissue-derived MSC (AT-MSC/hTNF) was tested on the tumour cell lines of different origins: melanoma (A375), breast carcinoma (SKBR3, MDA-MB-231), colon carcinoma (HT29), ovarian carcinoma (SKOV3) and glioblastoma (U87-MG) cells. The tumour suppressing effect of AT-MSC/hTNF on A375 melanoma xenografts was monitored in an immunodeficient mouse model in vivo. ResultsEngineered AT-MSC are able to constitutively secrete human TNF protein, induce apoptosis of tumour cell lines via caspase 3/7 activation and inhibit the tumour cell proliferation in vitro. Melanoma A375 and breast carcinoma SKBR3 cells were the most sensitive, and their proliferation in vitro was reduced by conditioned media produced by AT-MSC/hTNF to 60% and 40%, respectively. The previously reported tumour supportive effect of AT-MSC on subcutaneous A375 melanoma xenograft growth was neutralised and suppressed by engineered AT-MSC stably producing hTNF. When AT-MSC/hTNF were coinjected with A375 melanoma cells, the tumour mass inhibition was up to 97.5%. ConclusionsThe results of the present study demonstrate that tumour cells respond to hTNF-based treatment mediated by genetically engineered AT-MSC/hTNF both in vitro and in vivo. Copyright (c) 2015 John Wiley & Sons, Ltd.