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Loss of caveolin‐1 in prostate cancer stroma correlates with reduced relapse‐free survival and is functionally relevant to tumour progression
Author(s) -
Ayala Gustavo,
Morello Matteo,
Frolov Anna,
You Sungyong,
Li Rile,
Rosati Fabiana,
Bartolucci Gianluca,
Danza Giovanna,
Adam Rosalyn M,
Thompson Timothy C,
Lisanti Michael P,
Freeman Michael R,
Di Vizio Dolores
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4217
Subject(s) - stromal cell , prostate cancer , cancer research , stroma , biology , protein kinase b , pten , prostate , gene silencing , intracrine , metastasis , angiogenesis , cancer , pi3k/akt/mtor pathway , medicine , endocrinology , paracrine signalling , microbiology and biotechnology , signal transduction , immunology , immunohistochemistry , receptor , biochemistry , gene
Levels of caveolin‐1 (Cav‐1) in tumour epithelial cells increase during prostate cancer progression. Conversely, Cav‐1 expression in the stroma can decline in advanced and metastatic prostate cancer. In a large cohort of 724 prostate cancers, we observed significantly decreased levels of stromal Cav‐1 in concordance with increased Gleason score ( p = 0.012). Importantly, reduced expression of Cav‐1 in the stroma correlated with reduced relapse‐free survival ( p = 0.009), suggesting a role for stromal Cav‐1 in inhibiting advanced disease. Silencing of Cav‐1 by shRNA in WPMY ‐1 prostate fibroblasts resulted in up‐regulation of Akt phosphorylation, and significantly altered expression of genes involved in angiogenesis, invasion, and metastasis, including a > 2.5‐fold increase in TGF ‐β1 and γ‐synuclein ( SNCG ) gene expression. Moreover, silencing of Cav‐1 induced migration of prostate cancer cells when stromal cells were used as attractants. Pharmacological inhibition of Akt caused down‐regulation of TGF ‐β1 and SNCG , suggesting that loss of Cav‐1 in the stroma can influence Akt‐mediated signalling in the tumour microenvironment. Cav‐1‐depleted stromal cells exhibited increased levels of intracellular cholesterol, a precursor for androgen biosynthesis, steroidogenic enzymes, and testosterone. These findings suggest that loss of Cav‐1 in the tumour microenvironment contributes to the metastatic behaviour of tumour cells by a mechanism that involves up‐regulation of TGF ‐β1 and SNCG through Akt activation. They also suggest that intracrine production of androgens, a process relevant to castration resistance, may occur in the stroma. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.