Anti-tumor effects of canine adipose tissue-derived mesenchymal stromal cell-based interferon-β gene therapy and cisplatin in a mouse melanoma model

초록

Background aims. Adipose tissue (AT)-derived mesenchymal stromal cells (MSC) (AT-MSC) represent a novel tool for delivering therapeutic genes to tumor cells. Interferon (IFN)-beta is a cytokine with pleiotropic cellular functions, including anti-proliferative, immunomodulatory and anti-angiogenic activities. The purpose of this study was to engineer canine AT-MSC (cAT-MSC) producing IFN-beta and to evaluate the anti-tumor effect of cAT-MSC-IFN-beta combined with cisplatin in mouse melanoma model. Methods. cAT-MSC engineered to express mouse IFN-beta were generated using a lentiviral vector (cAT-MSC-IFN-beta) and the secreted IFN-beta-induced inhibition of tumor cell growth and apoptosis on B16F10 cells was investigated in vitro prior to in vivo studies. Melanoma-bearing mouse was developed by injecting B16F10 cells subcutaneously into 6-week-old C57BL/6 mice. After 14 days, cisplatin (10 mg/kg) was injected intratumorally, and 3 days later the engineered cAT-MSC were injected subcutaneously every 3 days to death. Tumor volume and survival times were measured. Results. The combination treatment of cAT-MSC-IFN-beta with cisplatin was more effective in inhibiting the growth of melanoma and resulted in significantly extended survival time than both an unengineered cAT-MSC-cisplatin combination group and a cisplatin-alone group. Interestingly, subcutaneously injected cAT-MSC-IFN-beta were migrated to tumor sites. Conclusions. Our data suggest that canine AT-MSC could serve as a powerful cell-based delivery vehicle for releasing therapeutic proteins to tumor lesions. Maximal anti-tumor effects were seen when this therapy was combined with a DNA-damaging chemotherapeutic agent. This study demonstrates the possible applicability of AT-MSC-mediated IFN-beta in treating canine and human cancer patients.

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