Mesenchymal stem cells seldomly fuse with hepatocellular carcinoma cells and are mainly distributed in the tumor stroma in mouse models

Li,Guo-Cai; Ye,Qing-Hai; Dong,Qiong-Zhu; Ren,Ning; Jia,Hu-Liang; Qin,Lun-Xiu

doi:10.3892/or.2012.2174

Mesenchymal stem cells seldomly fuse with hepatocellular carcinoma cells and are mainly distributed in the tumor stroma in mouse models

Authors:
- Guo-Cai Li
- Qing-Hai Ye
- Qiong-Zhu Dong
- Ning Ren
- Hu-Liang Jia
- Lun-Xiu Qin
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Affiliations: Liver Cancer Institute and Zhongshan Hospital, Institute of Biomedical Science, Fudan University, Shanghai, P.R. China
Published online on: December 10, 2012 https://doi.org/10.3892/or.2012.2174
Pages: 713-719

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Abstract

Mesenchymal stem cells (MSCs) can have an effect on the growth and metastasis of human malignancies, including hepatocellular carcinoma (HCC); however, their mechanisms of action are not yet fully understood. The cell fusion of stem cell derived from bone marrow with other cells has been increasingly emphasized. The purpose of this study was to investigate the distribution of MSCs in mouse models of HCC, as well as the cell fusion between MSCs and HCC cells. We labeled HCC cells and MSCs with green fluorescence protein (GFP), red fluorescence protein (RFP), 4',6-diamidino-2-phenylindole (DAPI) and 5-bromo-2'-deoxyuridine (BrdU). We found that MSCs fused with HCC cells at a low frequency in vitro. MSCs were found to be merged into HCC tissues after intravenous injection, and compared with the mice not injected with MSCs, the MSCs were mainly distributed in the tumor stroma; Following the injection of the MSCs, the tumor stroma was found to have expanded in size, and the rate of pulmonary metastasis in the MSC-injected group was significantly lower (20%) compared to that in the group not injected with MSCs (100%, P=0.01). These data suggest that cell fusion between MSCs and HCC after engraftment is not one of the main mechanisms of action of the MSCs, while stromal differentiation is a major mechanism of action of the MSCs, leading to the inhibition of the pulmonary metastasis of HCC.

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1	Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M and Bekele BN: Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst. 96:1593–1603. 2004. View Article : Google Scholar : PubMed/NCBI
2	Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL and Neel M: Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 5:309–313. 1999. View Article : Google Scholar : PubMed/NCBI
3	Beachy PA, Karhadkar SS and Berman DM: Tissue repair and stem cell renewal in carcinogenesis. Nature. 432:324–331. 2004. View Article : Google Scholar : PubMed/NCBI
4	Fierro FA, Sierralta WD, Epuñan MJ and Minguell JJ: Marrow-derived mesenchymal stem cells: role in epithelial tumor cell determination. Clin Exp Metastas. 21:313–319. 2004. View Article : Google Scholar : PubMed/NCBI
5	Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C and Chen Y: Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 80:267–274. 2006. View Article : Google Scholar : PubMed/NCBI
6	Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R and Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
7	Reyes M, Dudek A, Jahagirdan B, Koodie L, Marker PH and Verfaillie CM: Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest. 109:337–346. 2002. View Article : Google Scholar : PubMed/NCBI
8	Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noël D and Jorgensen C: Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 102:3837–3844. 2003. View Article : Google Scholar : PubMed/NCBI
9	Portolani N, Coniglio A, Ghidoni S, GiovanellMi A, Benetti G and Tiberio A: Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 243:229–235. 2006. View Article : Google Scholar
10	Ye QH, Qin LX, Forgues M, He P, Kim JW and Peng AC: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 9:416–423. 2003. View Article : Google Scholar
11	Alison MR and Lovell MJ: Liver cancer: the role of stem cells. Cell Prolif. 38:407–421. 2005. View Article : Google Scholar : PubMed/NCBI
12	Vassilopoulos G, Wang PR and Russell DW: Transplanted bone marrow regenerates liver by cell fusion. Nature. 422:901–904. 2003. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S and Grompe M: Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 422:897–901. 2003.PubMed/NCBI
14	Li GC, Ye QH, Xue YH, Sun HJ, Zhou HJ, Ren N, Jia HL, Shi J, Wu JC, Dai C, Dong QZ and Qin LX: Human mesenchymal stem cells inhibit metastasis of a hepatocellular carcinoma model using the MHCC97-H cell line. Cancer Sci. 101:2546–2553. 2010. View Article : Google Scholar : PubMed/NCBI
15	Nygren JM, Jovinge S, Breitbach M, Säwén P, Röll W, Hescheler J, Taneera J, Fleischmann BK and Jacobsen SE: Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med. 10:494–501. 2004. View Article : Google Scholar : PubMed/NCBI
16	Chen EH, Grote E, Mohler W and Vignery A: Cell-cell fusion. FEBS Lett. 581:2181–2193. 2007. View Article : Google Scholar : PubMed/NCBI
17	Ying QL, Nichols J, Chambers I and Smith A: BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 115:281–292. 2003. View Article : Google Scholar : PubMed/NCBI
18	Li Y, Tang Y, Ye L, Liu B, Liu K and Chen J: Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screening for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol. 129:43–51. 2003.
19	Li Y, Tang ZY, Ye SL, Liu YK, Chen J and Xue Q: Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol. 7:630–636. 2001.PubMed/NCBI
20	Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Matsuura A, Hamada H and Niitsu Y: Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 106:756–763. 2005. View Article : Google Scholar : PubMed/NCBI
21	Kozorovitskiy Y and Gould E: Stem cell fusion in the brain. Nat Cell Biol. 5:952–954. 2003. View Article : Google Scholar : PubMed/NCBI
22	Wang X, Willenbring H and Akkari Y: Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 42:2897–2901. 2003.
23	Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ and Alvarez-Buylla A: Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 425:968–973. 2003. View Article : Google Scholar : PubMed/NCBI
24	Menthena A, Deb N, Oertel M, Grozdanov PN, Sandhu J, Shah S, Guha C, Shafritz DA and Dabeva MD: Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells. 22:1049–1061. 2004.PubMed/NCBI
25	Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, Daniel DM, Ruggero D and Shmelkov SV: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 438:820–827. 2005. View Article : Google Scholar
26	Ball SG, Shuttleworth AC and Kielty CM: Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol. 36:598–606. 2004. View Article : Google Scholar : PubMed/NCBI
27	Iakova P, Awad SS and Timchenko NA: Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell. 113:495–506. 2003. View Article : Google Scholar : PubMed/NCBI
28	Wagemaker G, Neelis KJ and Wognum AW: Surface markers and growth factor receptors of immature hemopoie tic stem cell subsets. Stem Cells. 13(Suppl 1): 165–171. 1995.PubMed/NCBI
29	Zheng YW and Taniguchi H: Diversity of hepatic stem cells in the fetal and adult liver. Semin Liver Dis. 23:337–348. 2003. View Article : Google Scholar : PubMed/NCBI
30	Goldsborough MD, Tilkins ML, Price PJ, Lobo-Alfonso J, Morrison JR and Stevens ME: Serum-free culture of murine embryonic stem (ES) cells. Focus. 20:8–12. 1998.
31	Desmouliere A, Guyot C and Gabbiani G: The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol. 48:509–517. 2004. View Article : Google Scholar : PubMed/NCBI
32	De Wever O and Mareel M: Role of tissue stroma in cancer cell invasion. J Pathol. 200:429–447. 2003.PubMed/NCBI
33	Direkze NC and Alison MR: Bone marrow and tumour stroma: an intimate relationship. Hematol Oncol. 24:189–195. 2006. View Article : Google Scholar : PubMed/NCBI
34	Littlepage LE, Egeblad M and Werb Z: Coevolution of cancer and stromal cellular responses. Cancer Cell. 7:499–500. 2005. View Article : Google Scholar : PubMed/NCBI
35	Welm AL: TGFbeta primes breast tumor cells for metastasis. Cell. 33:27–28. 2008. View Article : Google Scholar : PubMed/NCBI