title: Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy.
abstract: OBJECTIVE
  Androgen deprivation therapy (ADT) commonly leads to incomplete cell death and the fate of persistent cells involves, in part, a senescent phenotype. Senescence is terminal growth arrest in response to cell stress that is characterized by increased lysosomal-β-galactosidase (GLB1) the origin of senescence associated-β-gal activity (SA-β-gal). In the current study senescence is examined in vivo after ADT use in a neoadjuvant trial.
  
  
  METHODS
  Tissue microarrays were generated from prostate cancer specimens (n = 126) from a multicenter neoadjuvant ADT trial. Arrays were subjected to multiplexed immunofluorescent staining for GLB1, Ki67, cleaved caspase 3 (CC3) and E-cadherin. Automated quantitative imaging was performed using Vectra™ and expression correlated with clinicopathologic features.
  
  
  RESULTS
  Tissue was analyzed from 59 patients treated with neoadjuvant ADT and 67 receiving no therapy preoperatively. Median follow-up was 85.3 mo and median ADT treatment was 5 mo. In PC treated with neoadjuvant ADT, GLB1 expression increased in intermediate Gleason score (GS 6-7; p = 0.001), but not high grade (GS 8-10) cancer. Significantly higher levels of GLB1 were seen in tissues undergoing neoadjuvant ADT longer than 5 months compared to untreated tissues (p = 0.002). In contrast, apoptosis significantly increased earlier (1-4 mo) after ADT treatment (p<0.5).
  
  
  CONCLUSIONS
  Increased GLB1 after neoadjuvant ADT occurs primarily among more clinically favorable intermediate grade cancers and enrichment of the phenotype occurs in a temporally prolonged fashion. Senescence may explain the persistence of PCa cells after ADT. Given concerns for the detrimental longer term presence of senescent cells, targeting these cells for removal may improve outcomes.
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Blute
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Damaschke
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.|University of Wisconsin Carbone Comprehensive Cancer Center, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: E Jason
authors.initials: EJ
authors.lastname: Abel
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.|University of Wisconsin Carbone Comprehensive Cancer Center, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Downs
authors.affiliation: University of Wisconsin Carbone Comprehensive Cancer Center, Highland Ave, Madison, Wisconsin, United States of America.|Department of Pathology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Urology University of Wisconsin School of Medicine and Public Health, Highland Ave, Madison, Wisconsin, United States of America.|University of Wisconsin Carbone Comprehensive Cancer Center, Highland Ave, Madison, Wisconsin, United States of America.|Environmental and Molecular Toxicology, University of Wisconsin, University Ave Madison, Wisconsin, United States of America.
authors.forename: David F
authors.initials: DF
authors.lastname: Jarrard
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D015703:Antigens, CD; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy / Q000379:methods*; D060787:Neoplasm Grading; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D046888:Tissue Array Analysis; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C061901:GLB1 protein, human; D001616:beta-Galactosidase; D017430:Prostate-Specific Antigen; C505407:CASP3 protein, human; D053148:Caspase 3