Tumor Biology

, Volume 36, Issue 7, pp 5667–5677 | Cite as

IL-6 originated from breast cancer tissue-derived mesenchymal stromal cells may contribute to carcinogenesis

  • Özlem Sağlam
  • Zehra Seda Ünal
  • Cansu Subaşı
  • Engin Ulukaya
  • Erdal KaraözEmail author
Research Article


Tumor microenvironment is an important factor, which sustains and promotes the tumors by inflammatory signals. Interleukin-6 (IL-6) is known as a multifunctional cytokine, which is a major activator of the signaling pathway of Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3). In this study, we aimed to investigate the effect of IL-6 in the tumor microenvironment on carcinogenesis. For this purpose, healthy breast tissue-derived stromal cells (HBT-SCs) and malign breast tissue-derived stromal cells (MBT-SCs) were co-cultured with MCF-7 (human breast adenocarcinoma cell line) cells using semipermeable membranes. The cell proliferation was monitored with water-soluble tetrazolium (WST) and carboxyfluorescein succinimidyl ester (CFSE) assays. Protein levels were measured by enzyme-linked immunosorbent assay (ELISA) and Western blot hybridization, while gene expressions were measured by real-time PCR. The results demonstrated that IL-6 protein levels increased significantly in the supernatants of MBT-SCs when they were co-cultured with MCF-7 cells. In accordance with this, the expression of IL-6 was significantly higher in MBT-SCs. Additionally, the expression of STAT3 in MCF-7 cells increased slightly when they were co-cultured with MBT-SCs. Considering together, there is an important interaction between tumor microenvironment and tumor cells mediated by IL-6 signaling. Thereby, the targeting on IL-6 signaling in the treatment of cancer might effectively prevent the tumor progression.


IL-6 Tumor microenvironment Mesenchymal stromal cells Breast cancer 



We thank Dr. Gulçin Gacar and Gülay Erman for their technical assistance. The authors are also grateful to Dr. Murat Kasap and Dr. Gökhan Duruksu for their helpful comments on this study. We are grateful to Neslihan Onder who is a lecturer for English literature at the University of Uludağ.

Ethical standards

All of the biological materials used in this study were collected after the approval of the Ethics Committee (2009/112 I.E. 13/18) of Kocaeli University

Conflicts of interest


Supplementary material

13277_2015_3241_MOESM1_ESM.doc (1.4 mb)
ESM 1 (DOC 1475 kb)


  1. 1.
    Mbeunkui F, Johann DJ. Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol. 2009;63:571–82.CrossRefPubMedGoogle Scholar
  2. 2.
    Place AE, Huh SJ, Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res. 2011;13:227.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ben-Baruch A. Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res. 2003;5:31–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6:17–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev. 2007;7:139–47.CrossRefGoogle Scholar
  6. 6.
    Senst C, Nazari-Shafti T, Kruger S, Bentrup KHZ, Dupin CL, Chaffin AE, et al. Prospective dual role of mesenchymal stem cells in breast tumor microenvironment. Breast Cancer Res Treat. 2013;137:69–79.CrossRefPubMedGoogle Scholar
  7. 7.
    Suzuki K, Sun R, Origuchi M, Kanehira M, Takahata T, Itoh J, et al. Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med. 2011;17:579–87.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Polyak K, Kalluri R. The role of the microenvironment in mammary gland development and cancer. Cold Spring Harb Perspect Biol. 2010. doi: 10.1101/cshperspect.a003244.Google Scholar
  9. 9.
    Hu M, Polyak K. Molecular characterisation of the tumor microenvironment in breast cancer. Eur J Cancer. 2008;44:2760–5.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ma X-J, Dahiya S, Richardson E, Erlander M, Sgroi DC. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Research. 2009; 11, doi:  10.1186/bcr2222.
  11. 11.
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–63. doi: 10.1038/nature06188.CrossRefPubMedGoogle Scholar
  12. 12.
    Sasser AK, Mundy BL, Smith KM, Studebaker AW, Axel AE, Haidet AM, et al. Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor microenvironments. Cancer Lett. 2007;254(2):255–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Parker NN, Siemann DW. The microenvironment in cancer. In: Siemann DW, editor. Tumor microenvironment. USA: Wiley; 2011. p. 1–6.Google Scholar
  14. 14.
    Miki Y, Ono K, Hata S, Suzuki T, Kumamoto H, Sasano H. The advantages of co-culture over mono cell culture in simulating in vivo environment. J Steroid Biochem Mol Biol. 2012;131:68–75.CrossRefPubMedGoogle Scholar
  15. 15.
    Rattigan Y, Hsu J-M, Mishra PJ, Glod J, Banerjee D. Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp Cell Res. 2010;316:3417–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Patel SA, Heinrich AC, Reddy BY, Srinivas B, Heidaran N, Rameshwar P. Breast cancer biology: the multifaceted roles of mesenchymal stem cells. J Oncol. 2008;2008:1–7.CrossRefGoogle Scholar
  17. 17.
    Marotta LLC, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44+ CD24 stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–35.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rhodes LV, Antoon JW, Muir SE, Elliott S, Beckman BS, Burow ME. Effects of human mesenchymal stem cells on ER-positive human breast carcinoma cells mediated through ER-SDF-1/CXCR4 crosstalk. Mol Cancer. 2010;9:295.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Peng Y, Li Z, Li Z. GRP78 secreted by tumor cells stimulates differentiation of bone marrow mesenchymal stem cells to cancer-associated fibroblasts. Biochem Biophys Res Commun. 2013;440(4):558–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Barcellos-de-Souza P, Gori V, Bambi F, Chiarugi P. Tumor microenvironment: bone marrow-mesenchymal stem cells as key players. Biochim Biophys Acta. 1836;2013:321–35.Google Scholar
  21. 21.
    Karaoz E, Akpinar B. Filling the gap in the relationship between cancer and stem cells. In: Turksen K, editor. Stem cells: current challenges and new directions. Stem cell biology and regenerative medicine. New York: Springer Science+Business Media; 2013. p. 225–51.CrossRefGoogle Scholar
  22. 22.
    Karaöz E, Okcu A, Ünal ZS, Subaşı C, Sağlam O, Duruksu G. Adipose tissue-derived mesenchymal stromal cells efficiently differentiate into insulin-producing cells in pancreatic islet microenvironment both in vitro and in vivo. Cytotherapy. 2013;15:557–70.CrossRefPubMedGoogle Scholar
  23. 23.
    Karaöz E, Genç ZS, Demircan PÇ, Aksoy A. Duruksu G. Protection of rat pancreatic islet function and viability by coculture with rat bone marrow-derived mesenchymal stem cells. Cell Death and Disease. 2010; 1:e36; doi:  10.1038/cddis.2010.14.
  24. 24.
    Khamis ZI, Sahab ZJ, Amy Sang Q. Active roles of tumor stroma in breast cancer metastasis. Int J Breast Cancer. 2012. doi: 10.1155/2012/574025.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Muehlberg FL, Song Y, Krohn A, Pinilla SP, Droll LH, Leng X, et al. Tissue-resident stem cells promote breast cancer growth and metastasis. Carcinogenesis. 2009;30:589–97.CrossRefPubMedGoogle Scholar
  26. 26.
    Chen M-F, Lin P-Y, Wu C-F, Chen W-C, Wu C-T. IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS One. 2013;8:1–10.CrossRefGoogle Scholar
  27. 27.
    Guan J, Chen J. Mesenchymal stem cells in the tumor microenvironment. Biomedical Rep. 2013;1:527–1.Google Scholar
  28. 28.
    Jotzu C, Alt E, Welte G, Li J, Hennessy BT, Devarajan E, et al. Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. Cell Oncol. 2011;34:55–67.CrossRefGoogle Scholar
  29. 29.
    Sırotkovıc-Skerlev M, Lin J-H, Hsu T-W, Su K, Wang C-W, Yang K-Y, et al. Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway. Lung Cancer. 2012;75:167–77.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Özlem Sağlam
    • 1
  • Zehra Seda Ünal
    • 1
  • Cansu Subaşı
    • 1
  • Engin Ulukaya
    • 2
  • Erdal Karaöz
    • 3
    Email author
  1. 1.Center for Stem Cell and Gene Therapies Research and Practice, Department of Stem CellKocaeli UniversityKocaeliTurkey
  2. 2.Department of Medical BiochemistryUludağ UniversityBursaTurkey
  3. 3.Liv Hospital, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell)İstanbulTurkey

Personalised recommendations