Cancer Microenvironment

, Volume 5, Issue 1, pp 83–93

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

  • Honor J. Hugo
  • Stephanie Lebret
  • Eva Tomaskovic-Crook
  • Nuzhat Ahmed
  • Tony Blick
  • Donald F. Newgreen
  • Erik W. Thompson
  • M. Leigh Ackland
Original Paper

DOI: 10.1007/s12307-012-0098-7

Cite this article as:
Hugo, H.J., Lebret, S., Tomaskovic-Crook, E. et al. Cancer Microenvironment (2012) 5: 83. doi:10.1007/s12307-012-0098-7

Abstract

Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a ‘wound that never heals’. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancer-associated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

Keywords

IL-6 Inflammation Mast cells EMT Breast cancer Stroma 

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Honor J. Hugo
    • 1
    • 7
  • Stephanie Lebret
    • 2
  • Eva Tomaskovic-Crook
    • 1
  • Nuzhat Ahmed
    • 3
    • 4
  • Tony Blick
    • 1
  • Donald F. Newgreen
    • 6
  • Erik W. Thompson
    • 1
    • 5
  • M. Leigh Ackland
    • 2
  1. 1.St Vincent’s Institute of Medical ResearchFitzroyAustralia
  2. 2.Centre for Cellular and Molecular Biology, School of Life and Environmental SciencesDeakin UniversityBurwoodAustralia
  3. 3.Women’s Cancer Research CentreRoyal Women’s HospitalParkvilleAustralia
  4. 4.Department of Obstetrics & GynaecologyUniversity of MelbourneParkvilleAustralia
  5. 5.Department of Surgery, St Vincent’s HospitalUniversity of MelbourneFitzroyAustralia
  6. 6.Embryology Laboratory, Murdoch Children’s Research InstituteRoyal Children’s HospitalParkvilleAustralia
  7. 7.VBCRC Invasion and Metastasis UnitSt Vincent’s InstituteFitzroyAustralia

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