The Senescence-Associated Secretory Phenotype Promotes Benign Prostatic Hyperplasia

Vital, Paz; Castro, Patricia; Tsang, Susan Van; Ittmann, Michael

doi:10.1016/j.ajpath.2013.11.015

Cited by 37 publications

(31 citation statements)

References 41 publications

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“…Second, oxidative DNA damage can lead to results cellular senescence in a subset of prostatic epithelial cells and secondary secretion of multiple cytokines due to the senescence associated secretory response. We have shown in prior studies [8,[29][30][31][32], based on multiple markers, that senescent epithelial cells are significantly increased in BPH tissues, as are cytokines that are up regulated as part of the senescence associated secretory response such as IL-1a and IL-8. The senescent epithelial cells are irregularly distributed within the epithelial acini, similar to the pattern seen in 8-OHdG immunohistochemistry.…”

Section: Discussionmentioning

confidence: 96%

Oxidative stress promotes benign prostatic hyperplasia

2015

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BACKGROUND 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 significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH. METHODS Levels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter. RESULTS Human BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls. CONCLUSIONS Oxidative stress and oxidative DNA damage are important in the pathogenesis of BPH.

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Section: Discussionmentioning

confidence: 96%

Oxidative stress promotes benign prostatic hyperplasia

2015

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“…These results are consistent with reports that senescent cells with persistent DNA damage or replicative exhaustion secrete cytokines, growth factors, proteases, and other factors that enhance cell proliferation through autocrine and paracrine activities . Increased inflammatory characteristics of irradiated cells conform to previous reports that GM‐CSF, IL‐1α, and IL‐8 levels are significantly higher in BPH tissue than transition‐zone normal prostate, and in late‐passage prostate epithelial cells than early‐passage cells . The pro‐inflammatory cytokine IL‐18 and IGF1‐binding IGFBP2 were reduced in irradiated BPH‐1 cells (Figure A‐iii; B‐ii).…”

Section: Resultsmentioning

confidence: 85%

“…Benign prostate hyperplasia epithelium is enriched for senescent cells . Cellular senescence is known to occur in the prostate and various other human tissues during normal aging, in progeric patients manifesting accelerated aging, and in the course of replicative exhaustion of passaged cell populations.…”

Section: Introductionmentioning

confidence: 99%

“…Senescence‐associated β‐galactosidase (SA‐βGal) activity at pH 6.0 is another marker for senescent cells . Cells of the BPH epithelium and late‐passage epithelial cells isolated from the normal prostate transition zone showed elevated p16/INK4a and SA‐βGal . The tumor‐suppressive potential of senescent cells is mitigated in some contexts by a senescence‐associated secretory phenotype (SASP).…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of prostate cells by the senescence phenotype of epithelial and stromal cells: Implication for benign prostate hyperplasia

2019

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Hyperproliferation of prostate transition‐zone epithelial and stromal cells leads to benign prostate hyperplasia (BPH), a prevalent pathology in elderly men. Senescent cells in BPH tissue induce a senescence‐associated secretory phenotype (SASP) which, by generating inflamed microenvironment and reactive stroma, promotes leukocyte infiltration, cellular hyperproliferation, and nodular prostate growth. We examined human prostate epithelial (BPH‐1, PNT‐1α) and stromal (HPS‐19I) cells for SASP induction by ionizing radiation and assessed SASP's impacts on cell proliferation and on signal transducers that promote cellular growth, proliferation, and survival. Radiation‐induced DNA damage led to cellular senescence, evident from elevated expression of senescence‐associated β‐galactosidase and the cell‐cycle inhibitor p16/INK4a. Clinical BPH tissue showed p16 accumulation. SASP induced mRNA expression for inflammatory cytokines (IL‐1α, IL‐6, IL‐8, TNF‐α); chemokines (GM‐CSF, CXCL12); metalloproteases (MMP‐1, MMP‐3, MMP‐10); growth factor binding IGFBP‐3. Media from irradiated epithelial or stromal cells enhanced BPH‐1 proliferation. ERK1/2 and AKT, which enhance cell growth/survival and STAT5, which facilitates cell cycle progression and leukocyte recruitment to epithelial microenvironment, were activated by SASP components. The radiation‐induced cellular senescence model can be a platform for identification of individual SASP components and pathways that drive BPH etiology/progression in vivo and targeting them may form the basis for novel BPH therapy.

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“…These include p53 (35,50) (53), and several SASP components (54,55). Some of these upregulated gene expressions critically control the cell senescence itself, and contributes to the aging process and age-related diseases (56)(57)(58).…”

Section: Specific Versus Overall Gene Expression Changes In Senescencementioning

confidence: 99%

Erratum to: From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes

et al. 2016

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The BMB Reports would like to correct in the reference of BMB Rep. 48(10), 549-558 titled "From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes". The REFERENCE should be corrected as red highlighting in this pages. This Erratum's doi is https://doi.org/10.5483/ BMBRep.2016.49.11.122. Cellular senescence is a process by which cells enter a state of permanent cell cycle arrest. It is commonly believed to underlie organismal aging and age-associated diseases. However, the mechanism by which cellular senescence contributes to aging and age-associated pathologies remains unclear. Recent studies showed that senescent cells exert detrimental effects on the tissue microenvironment, generating pathological facilitators or aggravators. The most significant environmental effector resulting from senescent cells is the senescence-associated secretory phenotype (SASP), which is constituted by a strikingly increased expression and secretion of diverse pro-inflammatory cytokines. Careful investigation into the components of SASPs and their mechanism of action, may improve our understanding of the pathological backgrounds of age-associated diseases. In this review, we focus on the differential expression of SASP-related genes, in addition to SASP components, during the progress of senescence. We also provide a perspective on the possible action mechanisms of SASP components, and potential contributions of SASP-expressing senescent cells, to age-associated pathologies.

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The Senescence-Associated Secretory Phenotype Promotes Benign Prostatic Hyperplasia

Cited by 37 publications

References 41 publications

Oxidative stress promotes benign prostatic hyperplasia

Oxidative stress promotes benign prostatic hyperplasia

Stimulation of prostate cells by the senescence phenotype of epithelial and stromal cells: Implication for benign prostate hyperplasia

Erratum to: From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes

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