Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells

Abstract

Most advanced solid tumors metastasize to different organs. However, no gene therapy effective for multiple tumors has yet been developed. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting multiple tumors. First, we confirmed that mouse MSCs preferentially migrate to multiple tumors of the lung in the Colon-26 (C-26) lung metastasis model. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF), by an adenoviral vector with an RGD motif. MSCs expressing NK4 (NK4-MSCs) strongly inhibited development of lung metastases in the C-26 lung metastasis model after systemic administration via a tail vein. Treatment with NK4-MSCs significantly prolonged survival of the C-26-tumorbearing mice by inhibiting tumor-associated angiogenesis and lymphangiogenesis and inducing apoptosis of the tumor cells. MSC-based gene therapy did not induce the severe adverse effects induced by conventional adenoviral vectors. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting multiple lung metastatic tumors.

Improved lentiviral transduction of human mesenchymal stem cells for therapeutic intervention in pancreatic cancer

“…Thus, application of MSC has no apparent adverse side effects, since the mice in our experiments looked healthy after administration of MSC, and another report demonstrated that MSC overexpressing the adenoviral-transduced NK4 gene did not lead to enhanced liver enzymes in serum. 35 Therefore, selective engraftment of MSC expressing an antitumor agent in the tumor tissues should be sufficiently therapeutically advantageous to warrant further clinical trials. However, practical realization of efficient gene transfer by MSC vehicles has been limited.…”

Therapeutic potential of genetically modified mesenchymal stem cells

“…43 Improved transduction of adenoviral vectors to MSC has been shown using modification to include the RGD (Arg-Gly-Asp) motif on the penton fiber. Adopting this strategy, Kanehira et al 44 transduced NK4, an antagonist of hepatocyte growth factor and significantly prolonged the survival of mice bearing colon-26 cell line xenograft in lungs by inhibiting angiogenesis and lymphangiogenesis and inducing apoptosis of tumor cells. Antitumor activity of retrovirus vector transduced MSC, producing IL-12, has been tested in a mouse melanoma model.…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…Instead, the most exciting and clinically relevant finding is that MSCs possess unique tumor-trophic, drug-resistant and migratory properties and overexpress efflux transporters such as P-glycoproteins [125]. These features have founded the rationale to develop MSCs as vehicles to deliver specific anti-angiogenic and anti-tumor agents [127,128]. These genetically engineered MSCs can successfully deliver an antagonist of the hepatocyte growth factor, the TNF-related apoptosis-inducing ligand (TRAIL) and IFN-a with potent anti-tumor effects both in vitro and in vivo [128][129][130].…”

“…These features have founded the rationale to develop MSCs as vehicles to deliver specific anti-angiogenic and anti-tumor agents [127,128]. These genetically engineered MSCs can successfully deliver an antagonist of the hepatocyte growth factor, the TNF-related apoptosis-inducing ligand (TRAIL) and IFN-a with potent anti-tumor effects both in vitro and in vivo [128][129][130]. However, concerns about their biosafety and feasibility has led to the development of MSCs containing drug loaded nanoparticles [131] whose therapeutic effectiveness depends on the specificity of their migration and engraftment and is enhanced by local radiotherapy [132].…”