Original Paper

Cancer Microenvironment

, Volume 5, Issue 1, pp 83-93

First online:

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

  • Honor J. HugoAffiliated withSt Vincent’s Institute of Medical ResearchVBCRC Invasion and Metastasis Unit, St Vincent’s Institute Email author 
  • , Stephanie LebretAffiliated withCentre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University
  • , Eva Tomaskovic-CrookAffiliated withSt Vincent’s Institute of Medical Research
  • , Nuzhat AhmedAffiliated withWomen’s Cancer Research Centre, Royal Women’s HospitalDepartment of Obstetrics & Gynaecology, University of Melbourne
  • , Tony BlickAffiliated withSt Vincent’s Institute of Medical Research
  • , Donald F. NewgreenAffiliated withEmbryology Laboratory, Murdoch Children’s Research Institute, Royal Children’s Hospital
  • , Erik W. ThompsonAffiliated withSt Vincent’s Institute of Medical ResearchDepartment of Surgery, St Vincent’s Hospital, University of Melbourne
  • , M. Leigh AcklandAffiliated withCentre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University

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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