Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells.
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-tumor-bearing 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.
Kanehira
M
M
Department of Molecular Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi Aobaku, Sendai, Japan.
Xin
H
H
Hoshino
K
K
Maemondo
M
M
Mizuguchi
H
H
Hayakawa
T
T
Matsumoto
K
K
Nakamura
T
T
Nukiwa
T
T
Saijo
Y
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology; D002465:Cell Movement; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000556:secondary / Q000628:therapy*; D042583:Lymphangiogenesis; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000628:therapy
C066855:HGF protein, human; D017228:Hepatocyte Growth Factor