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The senescence-associated secretory phenotype promotes benign prostatic hyperplasia.

ABSTRACT: Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and considerable morbidity in a majority of older men. Senescent cells accumulate in human tissues, including the prostate, with increasing age. Expression of proinflammatory cytokines is increased in these senescent cells, a manifestation of the senescence-associated secretory phenotype. Multiplex analysis revealed that multiple cytokines are increased in BPH, including GM-CSF, IL-1?, and IL-4, and that these are also increased in senescent prostatic epithelial cells in vitro. Tissue levels of these cytokines were correlated with a marker of senescence (cathepsin D), which was also strongly correlated with prostate weight. IHC analysis revealed the multifocal epithelial expression of cathepsin D and coexpression with IL-1? in BPH tissues. In tissue recombination studies in nude mice with immortalized prostatic epithelial cells expressing IL-1? and prostatic stromal cells, both epithelial and stromal cells exhibited increased growth. Expression of IL-1? in prostatic epithelial cells in a transgenic mouse model resulted in increased prostate size and bladder obstruction. In summary, both correlative and functional evidence support the hypothesis that the senescence-associated secretory phenotype can promote the development of BPH, which is the single most common age-related pathology in older men.

SUBMITTER: Vital P

PROVIDER: S-EPMC3936307 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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The senescence-associated secretory phenotype promotes benign prostatic hyperplasia.

Vital Paz P Castro Patricia P Tsang Susan S Ittmann Michael M

The American journal of pathology 20140113 3

Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and considerable morbidity in a majority of older men. Senescent cells accumulate in human tissues, including the prostate, with increasing age. Expression of proinflammatory cytokines is increased in these senescent cells, a manifestation of the senescence-associated secretory phenotype. Multiplex analysis revealed that multiple cytokin ...[more]

PMID: 24434012

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Project description:BackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

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The senescence-associated secretory phenotype promotes benign prostatic hyperplasia.

Publications

The senescence-associated secretory phenotype promotes benign prostatic hyperplasia.

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