title: Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression.
abstract: 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.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
authors.affiliation: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|The Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Morello
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Frolov
authors.affiliation: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Sungyong
authors.initials: S
authors.lastname: You
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Rile
authors.initials: R
authors.lastname: Li
authors.affiliation: Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rosati
authors.affiliation: Department of Pharmaceutical Sciences, University of Florence, Sesto Fiorentino, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolucci
authors.affiliation: Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Danza
authors.affiliation: The Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Department of Genitourinary Medical Oncology, Unit 18-3, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.affiliation: Breast Oncology and Institute of Cancer Sciences, Paterson Institute of Cancer Research, The University of Manchester, Manchester, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.affiliation: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|The Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Departments of Surgery and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|The Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Dolores Di
authors.initials: DD
authors.lastname: Vizio
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*; D015996:Survival Rate; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D051845:gamma-Synuclein / Q000378:metabolism
chemical_list: D015415:Biomarkers; C495540:CAV1 protein, human; D051242:Caveolin 1; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D051845:gamma-Synuclein; D051057:Proto-Oncogene Proteins c-akt
keywords: caveolin-1; prognosis; prostate cancer; stroma