Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer

Background aims. Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment. Methods. Using both syngeneic mouse tumors (ID8-R) and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed that intraperitoneally injected circulating mesenchymal stem cells (MSCs) could target, preferentially engraft and differentiate into alpha-smooth muscle actin-positive myofibroblasts, suggesting their role as "reactive stoma" in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-beta (IFN-beta). Mice with ovarian carcinomas then received weekly intraperitoneal injections of IFN-beta expressing MSCs. Results. Intraperitoneal injections of IFN-beta expressing MSCs resulted in complete eradication of tumors in 70% of treated OVCAR3 mice (P = 0.004) and an increased survival of treated SKOV3 mice compared with controls (P = 0.01). Similar tumor growth control was observed using murine IFN-beta delivered by murine MSCs in ID8-R ovarian carcinoma. As a potential mechanism of tumor killing, MSCs produced IFN-beta-induced caspase-dependent tumor cell apoptosis. Conclusions. Our results demonstrate that ovarian carcinoma engrafts MSCs to participate in myofibrovascular networks and that IFN-beta produced by MSCs intratumorally modulates tumor kinetics, resulting in prolonged survival.