Mesenchymal stem cells play a potential role in regulating the establishment and maintenance of epithelial-mesenchymal transition in MCF7 human breast cancer cells by paracrine and induced autocrine TGF-β

Xu,Qilin; Wang,Liang; Li,Hongling; Han,Qin; Li,Jing; Qu,Xuebin; Huang,Shan; Zhao,Robert  Chunhua

doi:10.3892/ijo.2012.1541

Mesenchymal stem cells play a potential role in regulating the establishment and maintenance of epithelial-mesenchymal transition in MCF7 human breast cancer cells by paracrine and induced autocrine TGF-β

Authors:
- Qilin Xu
- Liang Wang
- Hongling Li
- Qin Han
- Jing Li
- Xuebin Qu
- Shan Huang
- Robert Chunhua Zhao
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Affiliations: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, P.R. China, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, P.R. China
Published online on: July 3, 2012 https://doi.org/10.3892/ijo.2012.1541
Pages: 959-968

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Abstract

Although the epithelial-mesenchymal transition (EMT) is a normal process that occurs during development, it is thought to be associated with cancer progression and metastasis. Emerging evidence links mesenchymal stem cells (MSCs) in the tumor microenvironment with the occurrence of EMT in cancer progression. In this study, the human breast cancer cell line MCF7 was co-cultured with human adipose-derived MSCs (hAD-MSCs) in a transwell system. Co-cultured cells were analyzed for changes in cellular morphology, EMT markers, protein expression and tumor characteristics. We found that co-cultured MCF7 cells underwent EMT and established a stable mesenchymal phenotype after prolonged co-culturing. Here, we demonstrate that paracrine transforming growth factor-β1 (TGF-β1) secreted by hAD-MSCs regulated the establishment of EMT in MCF7 cells by targeting the ZEB/miR-200 regulatory loop. The downregulation of paracrine TGF-β1 levels can inhibit and reverse the EMT progress by downregulating ZEB1/2 and upregulating miR-200b and miR-200c. The maintenance of a stable mesenchymal state by MCF7 cells required the establishment of autocrine TGF-β signaling to drive and sustain ZEB expression, which had been initiated by the prolonged co-culturing with hAD-MSCs. These results suggest that MSCs may promote breast cancer metastasis by stimulating and facilitating the EMT process.

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1.	Gupta GP and Massague J: Cancer metastasis: building a framework. Cell. 127:679–695. 2006. View Article : Google Scholar : PubMed/NCBI
2.	Weigelt B, Peterse JL and van’t Veer LJ: Breast cancer metastasis: markers and models. Nat Rev Cancer. 5:591–602. 2005. View Article : Google Scholar : PubMed/NCBI
3.	Guarino M, Rubino B and Ballabio G: The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 39:305–318. 2007. View Article : Google Scholar : PubMed/NCBI
4.	Kang Y and Massague J: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 118:277–279. 2004. View Article : Google Scholar : PubMed/NCBI
5.	Trimboli AJ, Fukino K, de Bruin A, et al: Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res. 68:937–945. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Baum B, Settleman J and Quinlan MP: Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol. 19:294–308. 2008. View Article : Google Scholar : PubMed/NCBI
7.	Hugo H, Ackland ML, Blick T, et al: Epithelial-mesenchymal and mesenchymal - epithelial transitions in carcinoma progression. J Cell Physiol. 213:374–383. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Yang J and Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Brabletz T, Jung A, Spaderna S, Hlubek F and Kirchner T: Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 5:744–749. 2005. View Article : Google Scholar : PubMed/NCBI
11.	Mani SA, Guo W, Liao MJ, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
12.	Gupta PB, Chaffer CL and Weinberg RA: Cancer stem cells: mirage or reality? Nat Med. 15:1010–1012. 2009. View Article : Google Scholar : PubMed/NCBI
13.	Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI
14.	Hu M and Polyak K: Molecular characterisation of the tumour microenvironment in breast cancer. Eur J Cancer. 44:2760–2765. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Fierro FA, Sierralta WD, Epunan MJ and Minguell JJ: Marrow-derived mesenchymal stem cells: role in epithelial tumor cell determination. Clin Exp Metastasis. 21:313–319. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Hombauer H and Minguell JJ: Selective interactions between epithelial tumour cells and bone marrow mesenchymal stem cells. Br J Cancer. 82:1290–1296. 2000. View Article : Google Scholar : PubMed/NCBI
17.	Sasser AK, Mundy BL, Smith KM, et al: Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments. Cancer Lett. 254:255–264. 2007. View Article : Google Scholar
18.	Chen J, Zhang ZG, Li Y, et al: Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 92:692–699. 2003. View Article : Google Scholar : PubMed/NCBI
19.	Kumar S, Chanda D and Ponnazhagan S: Therapeutic potential of genetically modified mesenchymal stem cells. Gene Ther. 15:711–715. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Karnoub AE, Dash AB, Vo AP, et al: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
21.	Dwyer RM, Potter-Beirne SM, Harrington KA, et al: Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res. 13:5020–5027. 2007. View Article : Google Scholar : PubMed/NCBI
22.	Molloy AP, Martin FT, Dwyer RM, et al: Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions with breast cancer cells. Int J Cancer. 124:326–332. 2009. View Article : Google Scholar : PubMed/NCBI
23.	Zeisberg M and Kalluri R: The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med. 82:175–181. 2004. View Article : Google Scholar : PubMed/NCBI
24.	Pardali K and Moustakas A: Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 1775:21–62. 2007.PubMed/NCBI
25.	Derynck R and Akhurst RJ: Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol. 9:1000–1004. 2007. View Article : Google Scholar : PubMed/NCBI
26.	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
27.	Peinado H, Olmeda D and Cano A: Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 7:415–428. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Burk U, Schubert J, Wellner U, et al: A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9:582–589. 2008. View Article : Google Scholar : PubMed/NCBI
29.	Gregory PA, Bert AG, Paterson EL, et al: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI
30.	Park SM, Gaur AB, Lengyel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Bracken CP, Gregory PA, Kolesnikoff N, et al: A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68:7846–7854. 2008. View Article : Google Scholar : PubMed/NCBI
32.	Gregory PA, Bracken CP, Bert AG and Goodall GJ: MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle. 7:3112–3118. 2008. View Article : Google Scholar : PubMed/NCBI
33.	Cao Y, Sun Z, Liao L, Meng Y, Han Q and Zhao RC: Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 332:370–379. 2005. View Article : Google Scholar : PubMed/NCBI
34.	Gregory PA, Bracken CP, Smith E, et al: An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell. 22:1686–1698. 2011. View Article : Google Scholar : PubMed/NCBI
35.	Brabletz S and Brabletz T: The ZEB/miR-200 feedback loop - a motor of cellular plasticity in development and cancer? EMBO Rep. 11:670–677. 2010. View Article : Google Scholar : PubMed/NCBI