Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice.
BACKGROUND
The human umbilical cord mesenchymal stem cells (hUCMSCs) have the ability to migrate into tumors and therefore have been considered as an alternative source of mesenchymal progenitors for the therapy of malignant diseases. The present study was aimed to investigate effect of hUCMSCs as vehicles for a constant source of transgenic interleukin-21 (IL-21) on ovarian cancer in vivo.


METHODS
The hUCMSCs were engineered to express IL-21 via lentiviral vector- designated 'hUCMSCs-LV-IL-21', and then were transplanted into SKOV3 ovarian cancer xenograft-bearing nude mice. The therapeutic efficacy and mechanisms of this procedure on ovarian cancer was evaluated.


RESULTS
The isolated hUCMSCs were induced to differentiate efficiently into osteoblast and adipocyte lineages in vitro. The expressed IL-21 in the supernatant from hUCMSCs-LV-IL-21 obviously stimulated splenocyte's proliferation. The hUCMSCs-LV-IL-21 significantly reduced SKOV3 ovarian cancer burden in mice indicated by tumor sizes compared with control mice. The expressed IL-21 not only regulated the levels of IFN-γ and TNF-α in the mouse serum but also increased the expression of NKG2D and MIC A molecules in the tumor tissues. The down regulation of β-catenin and cyclin-D1 in the tumor tissues may refer to the inhibition of SKOV3 ovarian cancer growth in mice. In addition, hUCMSCs did not form gross or histological teratomas up to 60 days posttransplantation in murine lung, liver, stomach and spleen.


CONCLUSIONS
These results clearly indicate a safety and usability of hUCMSCs-LV- IL-21 in ovarian cancer gene therapy, suggesting the strategy may be a promising new method for clinical treatment of ovarian cancer.
Yunxia
Y
Zhang
Jing
J
Wang
Department of Gynecology & Obstetrics, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China. renmulan@seu.edu.cn.
Mulan
M
Ren
Miao
M
Li
Dengyu
D
Chen
Junsong
J
Chen
Fangfang
F
Shi
Xiaoying
X
Wang
Jun
J
Dou
D000818:Animals; D045744:Cell Line, Tumor; D036101:Cord Blood Stem Cell Transplantation; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D013997:Time Factors; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism; D000098546:Interleukin-21
C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D007378:Interleukins; D051176:beta Catenin; D019938:Cyclin D1; D000098546:Interleukin-21