Cell fusion between gastric epithelial cells and mesenchymal stem cells results in epithelial-to-mesenchymal transition and malignant transformation
Tóm tắt
The discovery of cancer stem cells and tumor heterogeneity prompted the exploration of additional mechanisms aside from genetic mutations for carcinogenesis and cancer progression. The aim of the present study was to investigate the effect of cell fusion between mesenchymal stem cells and the gastric epithelial cells in tumorigenesis. Cell fusion between cord blood mesenchymal stem cells and human gastric epithelial cells was performed in vitro. Cell scratch and transwell assays were performed to determine migration and invasion abilities of the hybrids. The expressions of epithelial-mesenchymal transition-related proteins and genes were analyzed by immunocytochemistry and real time quantitative PCR. Tumorigenesis of the hybrids was evaluated through in vivo inoculation in nude mice. Hybrids expressed the phenotypes of both donor cells. Aneuploidy was observed in 84.1% of cells. The hybrids showed increased proliferation, migration and invasion abilities compared with the parental cells. In addition, the expression of N-cadherin and vimentin in the hybrids was significantly higher than that of the epithelial cells, and the mRNA expression of the epithelial-mesenchymal transition-related genes, Twist and Slug, in the hybrids was also increased compared with that of the parental epithelial cells. Furthermore, the hybrids formed masses of epithelial origin with glandular structures in BALB/c nude mice. These findings suggest that cell fusion between gastric epithelial cells and mesenchymal stem cells may result in epithelial to mesenchymal transition and malignant transformation.
Tài liệu tham khảo
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.
He X, Tsang TC, Pipes BL, Ablin RJ, Harris DT. A stem cell fusion model of carcinogenesis. J Exp Ther Oncol. 2005;5(2):101–9.
Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Cancer Res. 2009;69(22):8536–9.
Duelli DM, Hearn S, Myers MP, Lazebnik Y. A primate virus generates transformed human cells by fusion. J Cell Biol. 2005;171(3):493–503.
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003;425(6961):968–73.
Duelli D, Lazebnik Y. Cell fusion: a hidden enemy? Cancer Cell. 2003;3(5):445–8.
Ke Y, Ning T, Wang B. [Establishment and characterization of a SV40 transformed human fetal gastric epithelial cell line-GES-1]. Zhonghua Zhong Liu Za Zhi. 1994;16(1):7–10.
Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.
Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.
Gao P, Zheng J. Oncogenic virus-mediated cell fusion: new insights into initiation and progression of oncogenic viruses--related cancers. Cancer Lett. 2011;303(1):1–8.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.
Ebben JD, Treisman DM, Zorniak M, Kutty RG, Clark PA, Kuo JS. The cancer stem cell paradigm: a new understanding of tumor development and treatment. Expert Opin Ther Targets. 2010;14(6):621–32.
Wang Y, Fan H, Zhou B, Ju Z, Yu L, Guo L, et al. Fusion of human umbilical cord mesenchymal stem cells with esophageal carcinoma cells inhibits the tumorigenicity of esophageal carcinoma cells. Int J Oncol. 2012;40(2):370–7.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.
Dave B, Mittal V, Tan NM, Chang JC. Epithelial-mesenchymal transition, cancer stem cells and treatment resistance. Breast Cancer Res. 2012;14(1):202.
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.
Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. 2008;121(Pt 6):727–35.
Kong D, Wang Z, Sarkar SH, Li Y, Banerjee S, Saliganan A, et al. Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells. 2008;26(6):1425–35.
Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFbeta in cancer. FEBS Lett. 2012;586(14):1959–70.
Powell AE, Anderson EC, Davies PS, Silk AD, Pelz C, Impey S, et al. Fusion between intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res. 2011;71(4):1497–505.