Fusion of HepG2 cells with mesenchymal stem cells increases cancer‑associated and malignant properties: An in vivo metastasis model

  • Authors:
    • Hong Li
    • Zhenqing Feng
    • Tom C. Tsang
    • Tian  Tang
    • Xiaoqin  Jia
    • Xianghui  He
    • Michael  E. Pennington
    • Michael  S. Badowski
    • Anna  K.M. Liu
    • Deyu  Chen
    • David  T. Harris
    • Jesse  Martinez
    • Linda  C. Meade-Tollin
  • View Affiliations

  • Published online on: June 13, 2014     https://doi.org/10.3892/or.2014.3264
  • Pages: 539-547
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

In the present study, we have tested the hypothesis that fusion between an altered cell and a mesenchymal stem cell produces a hybrid cell with enhanced characteristics associated with metastatic cancer cells, and we have developed a flexible model for investigating the mechanisms of metastasis. Human HepG2 cells with low metastatic potential were induced to fuse with rat bone marrow mesenchymal stem cells, and the progeny were compared with the parental cells for possession of enhanced in vitro and in vivo characteristics of malignant cells. Compared to the parental cells, the fused cells exhibited enhanced expression of E-cadherin, vimentin, Twist, Snail, matrix metalloproteinase 2 and 9 activities, aneuploidy and enhanced in vitro invasion and migration. In an in vivo xenograft assay, the fused cells generated increased numbers of metastatic liver and lung lesions. This model system is a flexible tool for investigation of the mechanisms of stem cell fusion in carcinogenesis and metastasis and for the discovery of new therapeutic targets to inhibit metastasis.

References

1 

Cairns J: Cancer, Science and Society. Freeman; San Francisco: 1978

2 

Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC and Clarke SJ: The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 88:218–230. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S and Mazzone M: Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene. Apr 22–2013.(Epub ahead of print). View Article : Google Scholar

5 

De Wever O, Demetter P, Mareel M and Bracke M: Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer. 123:2229–2238. 2008.PubMed/NCBI

6 

Mishra PJ, Mishra PJ, Glod JW and Banerjee D: Mesenchymal stem cells: flip side of the coin. Cancer Res. 69:1255–1258. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Hass R and Otte A: Mesenchymal stem cells as all-round supporters in a normal and neoplastic microenvironment. Cell Commun Signal. 10:262012. View Article : Google Scholar : PubMed/NCBI

8 

He X, Tsang TC, Pipes BL, Ablin RJ and Harris DT: A stem cell fusion model of carcinogenesis. J Exp Ther Oncol. 5:101–109. 2005.PubMed/NCBI

9 

Ding J, Jin W, Chen C, Shao Z and Wu J: Tumor associated macrophage x cancer cell hybrids may acquire cancer stem cell properties in breast cancer. PLoS One. 7:e419422012. View Article : Google Scholar : PubMed/NCBI

10 

Lu X and Kang Y: Cell fusion as a hidden force in tumor progression. Cancer Res. 69:8536–8539. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Lu X and Kang Y: Cell fusion hypothesis of the cancer stem cell. Adv Exp Med Biol. 714:129–140. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J and Teris AJ: Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer. 5:899–904. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Pawelek JM and Chakraborty AK: Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer. 8:377–386. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Soleimani M and Nadri S: A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc. 4:102–106. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Köhler G and Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 256:495–497. 1975.

16 

Yang MH, Chang SY, Chiou SH, Liu CJ, Chi CW, Chen PM, et al: Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene. 26:1459–1467. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Duelli D and Lazebnik Y: Cell fusion: a hidden enemy? Cancer Cell. 3:445–448. 2003. View Article : Google Scholar : PubMed/NCBI

18 

Gerling M, Nousiainen K, Hautaniemi S, Krüger S, Fritzsche B, Homann N, et al: Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis. Inflamm Bowel Dis. 19:691–703. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Luzzo KM, Wang Q, Purcell SH, Chi M, Jimenez PT, Grindler N, et al: High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One. 7:e492172012. View Article : Google Scholar : PubMed/NCBI

20 

Hanna MO, Zayed NA, Darwish H and Girgis SI: Asynchronous DNA replication and aneuploidy in lymphocytes of hepatocellular carcinoma patients. Cancer Genet. 205:636–643. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Pfau SJ and Amon A: Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep. 13:515–527. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Stein-Werblowsky R and Ablin RJ: Consideration of the possible etiology of prostatic cancer. II International Congress of Andrology, Tel Aviv, Israel. Israel J Med Sci. 17:abs. 743. 1981.

23 

Fan F, Samuel S, Evans KW, Lu J, Xia L, Zhou Y, et al: Overexpression of Snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 1:5–16. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Gavert N and Ben-Ze’ev A: Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med. 14:199–209. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Horikawa T, Yoshizaki T, Kondo S, Furukawa M, Kaizaki Y and Pagano JS: Epstein-Barr virus latent membrane protein 1 induces Snail and epithelial-mesenchymal transition in metastatic nasopharyngeal carcinoma. Br J Cancer. 104:1160–1167. 2011. View Article : Google Scholar

26 

Jordà M, Olmeda D, Vinyals A, Valero E, Cubillo E, Llorens A, et al: Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci. 118:3371–3385. 2005.PubMed/NCBI

27 

Parsons JT, Zetter B and Mohla S: Shifting paradigms in tumor metastasis: challenges and opportunities. Cancer Biol Ther. 1:582–585. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Goldstein RH, Weinberg RA and Rosenblatt M: Of mice and (wo)men: mouse models of breast cancer metastasis to bone. J Bone Miner Res. 25:431–436. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Sasai K, Sukezane T, Yanagita E, Nakagawa H, Hotta A, Itoh T and Akagi T: Oncogene-mediated human lung epithelial cell transformation produces adenocarcinoma phenotypes in vivo. Cancer Res. 71:2541–2549. 2011. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August 2014
Volume 32 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Li, H., Feng, Z., Tsang, T.C., Tang, T., Jia, X., He, X. ... Meade-Tollin, L.C. (2014). Fusion of HepG2 cells with mesenchymal stem cells increases cancer‑associated and malignant properties: An in vivo metastasis model. Oncology Reports, 32, 539-547. https://doi.org/10.3892/or.2014.3264
MLA
Li, H., Feng, Z., Tsang, T. C., Tang, T., Jia, X., He, X., Pennington, M. E., Badowski, M. S., Liu, A. K., Chen, D., Harris, D. T., Martinez, J., Meade-Tollin, L. C."Fusion of HepG2 cells with mesenchymal stem cells increases cancer‑associated and malignant properties: An in vivo metastasis model". Oncology Reports 32.2 (2014): 539-547.
Chicago
Li, H., Feng, Z., Tsang, T. C., Tang, T., Jia, X., He, X., Pennington, M. E., Badowski, M. S., Liu, A. K., Chen, D., Harris, D. T., Martinez, J., Meade-Tollin, L. C."Fusion of HepG2 cells with mesenchymal stem cells increases cancer‑associated and malignant properties: An in vivo metastasis model". Oncology Reports 32, no. 2 (2014): 539-547. https://doi.org/10.3892/or.2014.3264