Abstract
PurposeAndrogen 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 and materialsTissue 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.ResultsTissue 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).ConclusionsIncreased 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.
Highlights
Prostate cancer (PCa) thrives on circulating androgens and the initial step in managing advanced PCa is androgen deprivation therapy (ADT)
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
Higher levels of GLB1 were seen in tissues undergoing neoadjuvant ADT longer than 5 months compared to untreated tissues (p = 0.002)
Summary
Prostate cancer (PCa) thrives on circulating androgens and the initial step in managing advanced PCa is androgen deprivation therapy (ADT). While ADT remains an effective early treatment with 90% of patients demonstrating a response, the rate at which the majority of men will progress over several years to castrate-resistant prostate cancer (CRPC) varies. [4,5,6] The risk of progressing to CRPC increases 5-fold with every point increase in Gleason score.[3, 7, 8] In SWOG 9994, factors that predicted longer survival at the time of diagnosis included minimal disease, better performance status, lack of bone pain, lower Gleason score, and lower PSA level.[8] substantial interpatient variation in responses were noted in this trial, and only 13% of patients with longer-term survival were accurately predicted emphasizing limitations to using these clinicopathologic factors.[9]
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