Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment

Hugo, Honor J., Lebret, Stephanie, Tomaskovic-Crook, Eva, Ahmed, Nuzhat, Blick, Tony, Newgreen, Donald F., Thompson, Erik W. and Ackland, M. Leigh 2012, Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment, Cancer microenvironment, vol. 5, no. 1, pp. 83-93.

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Title Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment
Author(s) Hugo, Honor J.
Lebret, Stephanie
Tomaskovic-Crook, Eva
Ahmed, Nuzhat
Blick, Tony
Newgreen, Donald F.
Thompson, Erik W.
Ackland, M. Leigh
Journal name Cancer microenvironment
Volume number 5
Issue number 1
Start page 83
End page 93
Total pages 11
Publisher Springer Netherlands
Place of publication Dordrecht, The Netherlands
Publication date 2012-04
ISSN 1875-2292
1875-2284
Keyword(s) IL-6
inflammation
mast cells
EMT
breast cancer
stroma
Summary 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.
Language eng
Field of Research 111201 Cancer Cell Biology
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2012, Springer
Persistent URL http://hdl.handle.net/10536/DRO/DU:30049667

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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