A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment
A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment
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DOI：
10.1002/path.4386
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发表时间：
2014-09-01
影响因子：
7.3
通讯作者：
Risbridger, Gail P.
中科院分区：
文献类型：
--
作者：
Ellem, Stuart J.;Taylor, Renea A.;Risbridger, Gail P.
前列腺癌是雄激素依赖性的，受雄激素和雌激素的调节。肿瘤微环境也提供了调节控制，但在人类前列腺肿瘤界面的雄激素和雌激素之间的平衡和相互作用是未知的。这项研究揭示了雌激素在微环境中的核心和主导作用，促进了炎症细胞因子的促肿瘤循环，涉及癌相关成纤维细胞（CAF）招募肥大细胞。肥大细胞数量在人前列腺癌临床标本中增加，特别是在瘤周基质中。人肥大细胞也显示表达ER α和ER β，雌二醇直接刺激肥大细胞增殖和迁移以及改变的细胞因子/趋化因子表达。与正常前列腺成纤维细胞（NPF）相比，CAFs中的雌激素：雄激素平衡发生了显著变化，ER：AR表达显著增加。雄激素信号传导在CAF中也减少，而ER.而ER β转录活性则不然，这使得雌激素在肿瘤微环境中决定激素的作用。基因微阵列分析确定CXCL 12为CAFs中主要的雌激素驱动靶基因，CAFs通过CXCL 12以CXCR 4依赖的方式募集肥大细胞。总的来说，这些数据揭示了肿瘤微环境中的多细胞雌激素作用，并显示了在前列腺肿瘤界面的主导雌激素而不是雄激素信号传导。版权所有（C）2014大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
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 ER alpha and ER beta, 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 ER.. and ER beta 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. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.