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.

Caveolin-1 Expression is Associated with Tumor Size and Therapy Response in Wilms Tumor

“…20 But in the most other studies, loss of stromal Cav-1 expression in association with the high tumoral Cav-1 expression, has been reported to be closely related with poor outcome in different malignancies. 1,3,[12][13][14]16,18,21 Similarly we demonstrated that the Cav-1 expression in WT associate with histological grade and stage. However, in survival analysis, Cav-1 expression was not an independent prognostic factor for patient outcome.…”

“…[12][13][14][15][16][17][18][19][20] Most authors suggested that Cav-1 positive tumor cells served as tumor promoters by these signaling pathways. 3,[12][13][14][15][16][17][18][19] In the present study, we determined Cav-1 expression nearly in the half of tumors. But we couldn't determine any statistical significant relationship between the presence of Cav-1 expression in the tumor cells and the tumor behaviors.…”

Identification of Key Genes and Pathways in Renal Cell Carcinoma Through Expression Profiling Data

“…CAV1 is a tumor suppressor candidate and is a negative regulator of the Ras-p42/44 mitogen-activated kinase cascade. Loss of CAV1 in the tumour microenvironment contributes to the metastatic behaviour of tumour cells by up-regulation of TGF-β1 and SNCG through Akt activation [36]. Its expression is down-regulated in some tumors, however, many studies demonstrates that elevated expression of CAV1 is associated with tumor metastasis and a worse prognosis in several neoplasms, such as colon and urinary bladder cancer [37,38].…”

Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling

“…Conversely, current evidence indicates that caveolin-1 loss in prostate cancer-associated stroma contributes to the metastatic behavior of tumor cells in advanced and metastatic prostate cancer (35) and loss of caveolin-1 expression in the prostatic tumor-associated stroma is associated with high Gleason score (36). In clinical studies, significant downregulation of the protein in prostate stroma has been shown to mediate progression to the castration-resistant phase of prostate cancer through diverse pathways (37).…”