Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome
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Damien A. Leach1, Eleanor F. Need1, Roxanne Toivanen2, Andrew P. Trotta1, Helen M. Palenthorpe1, David J. Tamblyn3, Tina Kopsaftis3, Georgina M. England4, Eric Smith1, Paul A. Drew1,5, Carole B. Pinnock3, Peng Lee6, Jeff Holst7,8, Gail P. Risbridger2, Samarth Chopra3,9, Donald B. DeFranco10, Renea A. Taylor2,11 and Grant Buchanan1
1 The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia
2 Department of Anatomy and Development, Monash University, VIC, Australia
3 Urology Unit, Repatriation General Hospital, SA, Australia
4 Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, SA, Australia
5 School of Nursing and Midwifery, Flinders University, Bedford Park, SA, Australia
6 Department of Pathology and Urology, New York University, NY, USA
7 Origins of Cancer Laboratory, Centenary Institute, NSW, Australia
8 Sydney Medical School, University of Sydney, NSW, Australia
9 Department of Urology, St Vincent’s Hospital, Sydney and Garvan Institute, NSW, Australia
10 Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA
11 Department of Physiology, Monash University, VIC, Australia
Grant Buchanan, email:
Renea Taylor, email:
Keywords: prostate cancer, androgen receptor, stroma, fibroblasts, extracellular matrix
Received: December 04, 2014 Accepted: April 02, 2015 Published: April 19, 2015
Androgen receptor (AR) signaling in stromal cells is important in prostate cancer, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using patient-matched benign and malignant prostate samples, we show a significant association between low AR levels in cancer associated stroma and increased prostate cancer-related death at one, three and five years post-diganosis, and in tissue recombination models with primary prostate cancer cells that low stromal AR decreases castration-induced apoptosis. AR-regulation was found to be different in primary human fibroblasts isolated from adjacent to cancerous and non-cancerous prostate epithelia, and to represent altered activation of myofibroblast pathways involved in cell cycle, adhesion, migration, and the extracellular matrix (ECM). Without AR signaling, the fibroblast-derived ECM loses the capacity to promote attachment of both myofibroblasts and cancer cells, is less able to prevent cell-matrix disruption, and is less likely to impede cancer cell invasion. AR signaling in prostate cancer stroma appears therefore to alter patient outcome by maintaining an ECM microenvironment inhibitory to cancer cell invasion. This paper provides comprehensive insight into AR signaling in the non-epithelial prostate microenvironment, and a resource from which the prognostic and therapeutic implications of stromal AR levels can be further explored.
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