TY - JOUR
T1 - Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome
AU - Leach, Damien
AU - Need, Eleanor
AU - Toivanen, Roxanne
AU - Trotta, Andrew
AU - Palenthorpe, Helen
AU - Tamblyn, David
AU - Kopsaftis, Tina
AU - England, Georgina
AU - Smith, Eric
AU - Drew, Paul
AU - Pinnock, Carole
AU - Lee, Peng
AU - Holst, Jeff
AU - Risbridger, Gail
AU - Chopra, Samarth
AU - DeFranco, Donald
AU - Taylor, Renea
AU - Buchanan, Grant
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - Extracellular matrix
KW - Fibroblasts
KW - Prostate cancer
KW - Stroma
UR - http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=3873
UR - http://www.scopus.com/inward/record.url?scp=84937902220&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3873
DO - 10.18632/oncotarget.3873
M3 - Article
VL - 6
SP - 16135
EP - 16150
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 18
ER -