A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment

Stuart J Ellem, Renea A Taylor, Luc Furic, Ola Larsson, Mark Frydenberg, David W Pook, John S Pedersen, Bree Cawsey, Andrew Trotta, Eleanor F Need, Grant Buchanan, Gail P Risbridger

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERalpha and ERbeta, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERalpha and ERbeta transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface.
Original languageEnglish
Pages (from-to)86 - 98
Number of pages13
JournalJournal of Pathology
Volume234
Issue number1
DOIs
Publication statusPublished - 2014

Cite this

@article{1740a6b3ae9d4a8dbdf2184d18ea9c2f,
title = "A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment",
abstract = "Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERalpha and ERbeta, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERalpha and ERbeta transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface.",
author = "Ellem, {Stuart J} and Taylor, {Renea A} and Luc Furic and Ola Larsson and Mark Frydenberg and Pook, {David W} and Pedersen, {John S} and Bree Cawsey and Andrew Trotta and Need, {Eleanor F} and Grant Buchanan and Risbridger, {Gail P}",
year = "2014",
doi = "10.1002/path.4386",
language = "English",
volume = "234",
pages = "86 -- 98",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "Wiley-Blackwell",
number = "1",

}

A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment. / Ellem, Stuart J; Taylor, Renea A; Furic, Luc; Larsson, Ola; Frydenberg, Mark; Pook, David W; Pedersen, John S; Cawsey, Bree; Trotta, Andrew; Need, Eleanor F; Buchanan, Grant; Risbridger, Gail P.

In: Journal of Pathology, Vol. 234, No. 1, 2014, p. 86 - 98.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment

AU - Ellem, Stuart J

AU - Taylor, Renea A

AU - Furic, Luc

AU - Larsson, Ola

AU - Frydenberg, Mark

AU - Pook, David W

AU - Pedersen, John S

AU - Cawsey, Bree

AU - Trotta, Andrew

AU - Need, Eleanor F

AU - Buchanan, Grant

AU - Risbridger, Gail P

PY - 2014

Y1 - 2014

N2 - Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERalpha and ERbeta, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERalpha and ERbeta transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface.

AB - Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERalpha and ERbeta, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERalpha and ERbeta transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface.

UR - http://onlinelibrary.wiley.com/doi/10.1002/path.4386/pdf

U2 - 10.1002/path.4386

DO - 10.1002/path.4386

M3 - Article

VL - 234

SP - 86

EP - 98

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 1

ER -