The Inhibitory Effect of Mesenchymal Stem Cells with rAd-NK4 on Liver Cancer
Mesenchymal stem cells (MSCs) can migrate to the tumor site and integrate into the tumor tissue. As a delivery vehicle of antitumor factors, MSCs have been tried in various tumor therapies. NK4 can both inhibit the growth, metastasis, and invasion of tumor cells induced by hepatocyte growth factor (HGF) and suppress tumor angiogenesis that is independent on HGF/cellular-mesenchymal-to-transition factor pathway. Adenovirus can directly deliver NK4 for tumor treatment but may induce immunological rejection. We combined MSCs with an adenovirus vector to deliver NK4 for liver tumor treatment. This study detected the migration of MSCs to high metastasis liver carcinoma cells MHCC-97H in vitro, investigated the inhibitory effect of rAd-NK4-MSCs on the growth and metastasis of MHCC-97H cells, further explored the inhibitory mechanism of rAd-NK4-MSCs to MHCC-97H cell metastasis, and examined the inhibitory effect of rAd-NK4-MSCs on the migration of human umbilical vein endothelial cells (HUVECs) in vitro. In this study, migration experiment was used for the potential capacity of MSCs and inhibition on migration of rAd-NK4-MSCs. Western blot was used for detecting the inhibition mechanism of rAd-NK4-MSCs to MHCC-97H cells. And, animal transplantation experiment was used for the inhibition of rAd-NK4-MSCs in vivo. MSC migration assay showed MSCs can significantly migrate to MHCC-97H cells. Co-culture results indicated that rAd-NK4-MSCs significantly inhibited the proliferation and migration of MHCC-97H cells in vitro. Western blot results proved that rAd-NK4-MSCs inhibited MHCC-97H cell migration correlating with suppressing Erk1/2 phosphorylation. HUVEC migration experiment suggested that rAd-NK4-MSCs had a potential of inhibiting tumor angiogenesis. Animal transplantation experiment showed that the tumor growth was significantly inhibited in the rAd-NK4-MSC group. Taken together, this study proved that NK4-modified MSCs had an inhibitory effect on the growth and migration of MHCC-97H cells and tumor angiogenesis, which provided a new strategy for liver tumor target therapy.
KeywordsMSCs NK4 Adenovirus vector Liver cancer cells Inhibition
Basic fibroblast growth factor
Cellular-mesenchymal-to-epithelial transition factor
Granulocyte macrophage colony-stimulating factor
Hepatocyte growth factor
Herpes simplex virus thymidine kinase
Human umbilical vein endothelial cells
Mesenchymal stem cells
- NK cell
Natural kill cell
Recombinant adeno-associated virus
Tumor necrosis factor-related apoptosis-inducing ligand
Vascular endothelial growth factor
This work was supported by the National Natural Science Foundation of China (81201762) and the National High Technology Research and Development Program (863 Program) of China (2014AA021605).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
- 1.Friedenstein, A. J., Chailakhjan, R. K., & Lalykina, K. S. (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics, 3, 393–403.Google Scholar
- 9.Cipriani, P., Di Benedetto, P., Liakouli, V., et al. (2013). Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular-based therapy. Clinical and Experimental Immunology, 173, 195–206.CrossRefGoogle Scholar
- 27.Kuba, K., Matsumoto, K., Date, K., et al. (2000). HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Research, 60, 6737–6743.Google Scholar
- 34.Rosen, E. M., Zitnik, R. J., Elias, J. A., et al. (1993). The interaction of HGF-SF with other cytokines in tumor invasion and angiogenesis. EXS, 65, 301–310.Google Scholar