Therapeutic potential of bone marrow-derived mesenchymal stem cells producing pigment epithelium-derived factor in lung carcinoma

Abstract

Abstract. Specific and efficient gene delivery to target cells and the subsequent expression of the RNA and protein is crucial to the success of gene-based therapy for cancer. Mesenchymal stem cells (MSCs) represent novel and efficient tools for delivery of therapeutic agents to tumor cells. In this study, we evaluated the potential of bone marrow-derived mesenchymal stem cells, genetically modified to express pigment epithelium-derived factor (PEDF) for the treatment of Lewis lung carcinoma (LLC). MSCs derived from murine bone marrow were efficiently engineered to express human PEDF by adenoviral transduction, and the expression and bioactivity of the transgenic protein from engineered MSCs were confirmed in vitro. Animal experiments showed that the systemic administration of MSCs treated with PEDF dramatically reduced the growth of LLC tumors and significantly prolonged survival. Immunohistochemistry analysis of the tumors from MSC-PEDF-treated animals indicated an increase in apoptosis and a decrease in microvessel density. ELISA showed that the group of MSCs treated with PEDF had relatively higher expression levels of PEDF in tumor tissue and lower levels in serum compared with the free Ad-PEDF group. These results suggest that MSCs have potential use as effective delivery of vehicles for therapeutic genes in the treatment of LLC.

The secretion profile of mesenchymal stem cells and potential applications in treating human diseases

“… 165 The genetically modified MSCs that highly express PEDF provide a more satisfactory outcome in preventing lung carcinoma progression. 247 The MSCs that deliver CXCL9 and OX40 ligand, as well as the CCL19-expressing MSCs, could increase the infiltration of CCR7 + DCs, CD8 + T cells, and NK cells in tumor sites to elicit their anti-tumor effects. 248 , 249 Additionally, MSC(BM)s could internalize antibiotics such as ciprofloxacin (CPX) and then release CPX to inhibit bacterial activity.…”

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

“…Consequently, substantial efforts are currently underway to optimize the use of exogenous PEDF for cancer treatment. These strategies are primarily focused in two areas: the development of protein or peptide therapeutics with enhanced antitumorigenic activity, such as PEDF phosphomimetics 73 , PEDF variant forms 78 or discrete PEDF-derived peptides that recapitulate the anticancer activity of full-length PEDF 35,36 ; and the establishment of efficient methods for PEDF administration that take advantage of delivery systems using either viral vectors directly 54,63,64,68,141–143 , virally infected human mesenchymal stem cells 144–146 , microparticles or nanoparticles of various compositions 71,147,148 or implanted micro-osmotic pumps 149 . Moreover, combination therapeutic protocols using PEDF in addition to differentiation-inducing agents such as IL-6 (REF.…”

Bone Marrow-Derived Mesenchymal Stem Cells Expressing Thioredoxin 1 Attenuate Bleomycin-Induced Skin Fibrosis and Oxidative Stress in Scleroderma

“…Therefore, engineered BMSCs represent ideal vectors for the transfer of genes to damaged endothelial cells in patients with SSc. Target transgenes have been expressed in BMSCs in vitro and transplanted into animal models, where differentiation and long-term transgene expression was observed (Chen et al, 2012). The thioredoxin (Trx) system is one of the principal intracellular redox systems (Holmgren, 2000).…”