Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome

Damien A Leach, Eleanor F Need, Roxanne Toivanen, Andrew Trotta, Helen M Palenthorpe, David J Tamblyn, Tina Kopsaftis, Georgina M England, Eric Smith, Paul A Drew, Carole B Pinnock, Peng Lee, Jeff Holst, Gail P Risbridger, Samarth Chopra, Donald B DeFranco, Renea A Taylor, Grant Buchanan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)16135 - 16150
Number of pages16
JournalOncotarget
Volume6
Issue number18
DOIs
Publication statusPublished - 2015

Cite this

Leach, D. A., Need, E. F., Toivanen, R., Trotta, A., Palenthorpe, H. M., Tamblyn, D. J., ... Buchanan, G. (2015). Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome. Oncotarget, 6(18), 16135 - 16150. https://doi.org/10.18632/oncotarget.3873
Leach, Damien A ; Need, Eleanor F ; Toivanen, Roxanne ; Trotta, Andrew ; Palenthorpe, Helen M ; Tamblyn, David J ; Kopsaftis, Tina ; England, Georgina M ; Smith, Eric ; Drew, Paul A ; Pinnock, Carole B ; Lee, Peng ; Holst, Jeff ; Risbridger, Gail P ; Chopra, Samarth ; DeFranco, Donald B ; Taylor, Renea A ; Buchanan, Grant. / Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome. In: Oncotarget. 2015 ; Vol. 6, No. 18. pp. 16135 - 16150.
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abstract = "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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Leach, DA, Need, EF, Toivanen, R, Trotta, A, Palenthorpe, HM, Tamblyn, DJ, Kopsaftis, T, England, GM, Smith, E, Drew, PA, Pinnock, CB, Lee, P, Holst, J, Risbridger, GP, Chopra, S, DeFranco, DB, Taylor, RA & Buchanan, G 2015, 'Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome' Oncotarget, vol. 6, no. 18, pp. 16135 - 16150. https://doi.org/10.18632/oncotarget.3873

Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome. / Leach, Damien A; Need, Eleanor F; Toivanen, Roxanne; Trotta, Andrew; Palenthorpe, Helen M; Tamblyn, David J; Kopsaftis, Tina; England, Georgina M; Smith, Eric; Drew, Paul A; Pinnock, Carole B; Lee, Peng; Holst, Jeff; Risbridger, Gail P; Chopra, Samarth; DeFranco, Donald B; Taylor, Renea A; Buchanan, Grant.

In: Oncotarget, Vol. 6, No. 18, 2015, p. 16135 - 16150.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome

AU - Leach, Damien A

AU - Need, Eleanor F

AU - Toivanen, Roxanne

AU - Trotta, Andrew

AU - Palenthorpe, Helen M

AU - Tamblyn, David J

AU - Kopsaftis, Tina

AU - England, Georgina M

AU - Smith, Eric

AU - Drew, Paul A

AU - Pinnock, Carole B

AU - Lee, Peng

AU - Holst, Jeff

AU - Risbridger, Gail P

AU - Chopra, Samarth

AU - DeFranco, Donald B

AU - Taylor, Renea A

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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/25965833

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

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