Effect of bone-marrow-derived mesenchymal stem cells on high-potential hepatocellular carcinoma in mouse models: an intervention study.
BACKGROUND
There are two completely contradictory views regarding the impact of human bone-marrow-derived mesenchymal stem cells (hMSCs) on hepatocellular carcinomas (HCCs). The aim of this study was to investigate the effect of hMSC engraftment on HCC tissues in nude mouse models, and assess the effect on metastatic potential of HCC.


METHODS
hMSCs were engrafted into the nude mouse models of high metastatic HCC via the tail vein. The mice in the experimental group were engrafted with hMSCs (5 × 105 cells per mouse) via the tail vein 15 days after inoculation of tumor cells, twice a week, while the animals in the control group were injected with hMSC culture medium (0.2 mL per mouse) via the tail vein. The subcutaneous tumor size was measured using an electronic digital caliper once every 4 days after hMSC engraftment. After 2, 3, 4, 5 and 6 weeks of tumor cell inoculation, the mice were killed and the tumors were collected in their entirety. The tumor weights and body weights of mice were measured, and the tumor inhibition rate was calculated. Quantitative real-time polymerase chain reaction (RT-PCR) was used to determine the expression of metastasis-related genes including osteopontin (OPN), bone sialoprotein (BSP) and integrin α5 subunit (α-V) in the mouse models of high-metastatic HCC, and the expression of apoptosis-related genes including B cell lymphoma/leukemia-2 (Bcl2), Bcl-2 associated X protein (Bax) and caspase 3 in tumor samples.


RESULTS
The tumor weight inhibition rate was 26.62% at 2 weeks, 52.00% at 3 weeks, 38.20% at 4 weeks, 31.98% at 5 weeks, and 30.23% at 6 weeks. Tumor tissue weight comparison results were significantly lower in the hMSC engraftment groups than in the control group at the second and third weeks. The expression of metastasis-related factors OPN, BSP and α-V gene was downregulated with time. The expression of antiapoptotic gene Bcl2 exhibited an obvious declining tendency, while the expression of apoptotic genes Bax and caspase 3 showed an obvious rising tendency. The expression of α-V and BSP significantly correlated positively with the expression of Bcl2, and negatively correlated with the expression of Bax and caspase 3. The tumor inhibition rate was not significantly correlated with the expression of antiapoptotic and apoptotic factors, and α-V and BSP factors, though it exhibited a significantly negative correlation with the expression of OPN.


CONCLUSIONS
The highest tumor inhibition rate was observed 3 weeks after hMSCs engraftment, and the tumor inhibition rate gradually reduced with the progression of time. The metastatic potential of tumor cells was downregulated after hMSC engraftment and hMSCs induce further tumor cells apoptosis. The decrease in the proliferation ability of tumor cells may induce a decline in metastatic potential in tumor cells.
Department of Radiology, The 95th Hospital of PLA, PuTian, FuJian Province 351100, China. lizhaoruixin@sina.com.
Tianran
T
Li
Bin
B
Song
Xiangke
X
Du
Zhengmao
Z
Wei
Tianlong
T
Huo
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays