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 α-smooth muscle actin-positive myofibroblasts, suggesting their role as "reactive stroma" in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-ß (IFN-ß). Mice with ovarian carcinomas then received weekly intraperitoneal injections of IFN-ß expressing MSCs. RESULTS: Intraperitoneal injections of IFN-ß 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-ß delivered by murine MSCs in ID8-R ovarian carcinoma. As a potential mechanism of tumor killing, MSCs produced IFN-ß-induced caspase-dependent tumor cell apoptosis. CONCLUSIONS: Our results demonstrate that ovarian carcinoma engrafts MSCs to participate in myofibrovascular networks and that IFN-ß produced by MSCs intratumorally modulates tumor kinetics, resulting in prolonged survival.

Adipose-derived mesenchymal stem cells enhance healing of mandibular defects in the ramus of swine.

PURPOSE: This study investigated the effect of adipose-derived mesenchymal stem cells (ASCs) injected locally or systemically on the bone regeneration of a 10-mm-diameter cylindrical noncritical-size defect in the ramus of the pig mandible. MATERIALS AND METHODS: Fifteen Yorkshire pigs, weighing 60 to 80 kg, received bilateral 10-mm-diameter cylindrical surgical defects in each ramus of the mandible. Pigs received 1) a direct injection into the defect of 2.5 million carboxy-fluorescein diacetate succinimidyl ester-labeled ASCs from 1 of 2 pig donors (n = 6); 2) an ear vein injection of 5 million carboxy-fluorescein diacetate succinimidyl ester-labeled ASCs from 1 of 2 pig donors (n = 6); or 3) an ear vein injection of culture Dulbecco's Modified Eagle's Medium without stem cells (control; n = 3). Pigs from each treatment were sacrificed at 1 hour, 2 weeks, or 4 weeks after surgery. Healing of the defect was evaluated by dual-energy x-ray absorptiometry, micro-computed tomography, fluorescent microscopy, and histology. RESULTS: Bone healing was accelerated in the ASC-injected treatment groups at 2 and 4 weeks after surgery compared with the control pigs. CONCLUSIONS: Results from this animal model provide evidence that the injection of ASC locally into a bone defect or systemically can accelerate the healing of bone.