title: Overexpression of the novel senescence marker β-galactosidase (GLB1) in prostate cancer predicts reduced PSA recurrence.
abstract: OBJECTIVE
  Senescence is a terminal growth arrest that functions as a tumor suppressor in aging and precancerous cells and is a response to selected anticancer compounds. Lysosomal-β-galactosidase (GLB1) hydrolyzes β-galactose from glycoconjugates and is the origin of senescence-associated β-gal activity (SA-β-gal). Using a new GLB1 antibody, senescence biology was investigated in prostate cancer (PCa) tissues.
  
  
  METHODS
  In vitro characterization of GLB1 was determined in primary prostate epithelial cell cultures passaged to replicative senescence and in therapy-induced senescence in PCa lines using chemotherapeutic agents. FFPE tissue microarrays were subjected to immunofluorescent staining for GLB1, Ki67 and HP1γ and automated quantitative imaging initially using AQUA in exploratory samples and Vectra in a validation series.
  
  
  RESULTS
  GLB1 expression accumulates in replicative and induced senescence and correlates with senescent morphology and P16 (CDKN2) expression. In tissue arrays, quantitative imaging detects increased GLB1 expression in high-grade prostatic intraepithelial neoplasia (HGPIN), known to contain senescent cells, and cancer compared to benign prostate tissues (p<0.01) and senescent cells contain low Ki67 and elevated HP1γ. Within primary tumors, elevated GLB1 associates with lower T stage (p=0.01), localized versus metastatic disease (p=0.0003) and improved PSA-free survival (p=0.03). Increased GLB1 stratifies better PSA-free survival in intermediate grade PCa (0.01). Tissues that elaborate higher GLB1 display increased uniformity of expression.
  
  
  CONCLUSIONS
  Increased GLB1 is a valuable marker in formalin-fixed paraffin-embedded (FFPE) tissues for the senescence-like phenotype and associates with improved cancer outcomes. This protein addresses a lack of senescence markers and should be applicable to study the biologic role of senescence in other cancers.
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Jennifer
authors: J
authors: Wagner
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Nathan
authors: N
authors: Damaschke
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Bing
authors: B
authors: Yang
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Matthew
authors: M
authors: Truong
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Chad
authors: C
authors: Guenther
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Johnathon
authors: J
authors: McCormick
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Wei
authors: W
authors: Huang
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: David
authors: D
authors: Jarrard
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001388:Aziridines / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005557:Formaldehyde; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007610:Kallikreins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D016612:Paraffin Embedding; D061251:Primary Cell Culture; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D016019:Survival Analysis; D016707:Tissue Fixation; D001616:beta-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; D015415:Biomarkers; D005557:Formaldehyde; C061901:GLB1 protein, human; D001616:beta-Galactosidase; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C029108:diaziquone