IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures

Xie,Guozhu; Yao,Qiwei; Liu,Ying; Du,Shasha; Liu,Aihua; Guo,Zhaoze; Sun,Aimin; Ruan,Jian; Chen,Longhua; Ye,Changsheng; Yuan,Yawei

doi:10.3892/ijo.2011.1275

IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures

Authors:
- Guozhu Xie
- Qiwei Yao
- Ying Liu
- Shasha Du
- Aihua Liu
- Zhaoze Guo
- Aimin Sun
- Jian Ruan
- Longhua Chen
- Changsheng Ye
- Yawei Yuan
View Affiliations

Affiliations: Departments of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: November 30, 2011 https://doi.org/10.3892/ijo.2011.1275
Pages: 1171-1179

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recently, the inflammatory cytokine IL-6 has been reported as a potent inducer of epithelial-mesenchymal transition (EMT) in breast cancer cells with an epithelial phenotype. Furthermore, EMT induces stem cell features in normal and transformed mammary cells. We explored whether IL-6-induced EMT promoted the generation of breast cancer stem-like cells (BrCSCs) in epithelial-like breast cancer cells, and whether the cytokines EGF and bFGF, analogous to IL-6, per se induced epithelial-mesenchymal transition, resulting in the enrichment of BrCSCs in mammosphere cultures. Herein, we provide evidence that IL-6 is capable of generating CD44+ cells with stem-like properties through induction of the EMT in the epithelial-like T47D breast cancer cells. We also show that mammosphere cultures of epithelial-like breast cancer cells, T47D, MCF7, ZR-75-1 and MDA-MB-453 cells, consistently generated stem-like cancer cells solely as a result of the EGF and bFGF cytokines in the mammosphere media mediating EMT. This finding demonstrated the link between the inflammatory cytokine IL-6 and BrCSCs and identified an important mechanism for the enrichment of BrCSCs in mammosphere cultures. Thus, EMT appears to be a critical mechanism for the induction of cancer cells with stem-like properties, and EMT of non-stem cancer cells could be a source of CSCs.

View Figures

View References

1	Hodge DR, Hurt EM and Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 41:2502–2512. 2005.
2	Rose-John S, Scheller J, Elson G and Jones SA: Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 80:227–236. 2006.
3	Chavey C, Bibeau F, Gourgou-Bourgade S, et al: Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 9:R152007.
4	Kozlowski L, Zakrzewska I, Tokajuk P and Wojtukiewicz MZ: Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst. 48:82–84. 2003.
5	Bachelot T, Ray-Coquard I, Menetrier-Caux C, Rastkha M, Duc A and Blay JY: Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer. 88:1721–1726. 2003.
6	Ailles LE and Weissman IL: Cancer stem cells in solid tumors. Curr Opin Biotechnol. 18:460–466. 2007.
7	Rosen JM and Jordan CT: The increasing complexity of the cancer stem cell paradigm. Science. 324:1670–1673. 2009.
8	Shackleton M, Quintana E, Fearon ER and Morrison SJ: Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 138:822–829. 2009.
9	Al-Ejeh F, Smart CE, Morrison BJ, et al: Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis. 32:650–658. 2011.
10	Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 100:3983–3988. 2003.
11	Sullivan NJ, Sasser AK, Axel AE, et al: Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 28:2940–2947. 2009.
12	Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S and Puisieux A: Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 3:e28882008.
13	Mani SA, Guo W, Liao MJ, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008.
14	Prevo R, Deutsch E, Sampson O, et al: Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res. 68:5915–5923. 2008.
15	Phillips TM, McBride WH and Pajonk F: The response of CD24(−/low)/CD44⁺ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 98:1777–1785. 2006.
16	Van Phuc P, Nhan PL, Nhung TH, et al: Downregulation of CD44 reduces doxorubicin resistance of CD44CD24 breast cancer cells. Onco Targets Ther. 4:71–78. 2011.
17	Ponti D, Costa A, Zaffaroni N, et al: Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65:5506–5511. 2005.
18	De Visser KE and Coussens LM: The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. 13:118–137. 2006.
19	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001.
20	Li F, Tiede B, Massague J and Kang Y: Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res. 17:3–14. 2007.
21	Yu F, Yao H, Zhu P, et al: let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 131:1109–1123. 2007.
22	Hay ED: The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn. 233:706–720. 2005.
23	Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 15:740–746. 2003.
24	Dontu G, Abdallah WM, Foley JM, et al: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17:1253–1270. 2003.
25	Ackland ML, Newgreen DF, Fridman M, et al: Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest. 83:435–448. 2003.
26	Strutz F, Zeisberg M, Ziyadeh FN, et al: Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 61:1714–1728. 2002.