Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment.
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.
St Vincent's Institute of Medical Research, Fitzroy, Australia. hhugo@svi.edu.au.|VBCRC Invasion and Metastasis Unit, St Vincent's Institute, 9 Princes St, Fitzroy, 3065, Victoria, Australia. hhugo@svi.edu.au.
Honor J
HJ
Hugo
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood Campus, Burwood, Australia.
Stephanie
S
Lebret
St Vincent's Institute of Medical Research, Fitzroy, Australia.
Eva
E
Tomaskovic-Crook
Women's Cancer Research Centre, Royal Women's Hospital, Parkville, Australia.|Department of Obstetrics & Gynaecology, University of Melbourne, Parkville, Australia.
Nuzhat
N
Ahmed
St Vincent's Institute of Medical Research, Fitzroy, Australia.
Tony
T
Blick
Embryology Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
Donald F
DF
Newgreen
St Vincent's Institute of Medical Research, Fitzroy, Australia.|Department of Surgery, St Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
Erik W
EW
Thompson
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood Campus, Burwood, Australia.
M Leigh
ML
Ackland