Nastiuk, K. L. | Search bioRxiv

bioRxiv2021

Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer

Androgen deprivation therapy (ADT) induces regression of recurrent and advanced prostate cancer (PrCa), but many tumors recur. To understand the response to ADT, changes in tumor volume were imaged after castration of murine PrCa models. While mouse (non-tumor) prostate begins to regress within two days of castration, murine PrCa regresses after a delay of 3-14 days in two distinct mouse models. Intra-tumoral androgens are undetectable after castration, but tumor cells proliferate during this period. Intratumoral glucocorticoids and glucocorticoid receptor (GR) protein increase, as does GR mRNA and a set of GR-regulated genes specifically in tumor epithelial cells identified using scRNAseq. A selective GR antagonist (CORT125281, relacorilant), in clinical trials for late-state PrCa, eliminates the delayed regression phenotype in both models. Thus, activated GR signaling and murine tumor proliferation following castration resembles the GR-dependent escape mechanism of castrate resistant PrCa. These results suggest simultaneous inhibition of GR and androgen receptor signaling could improve PrCa therapy. In briefAndrogen deprivation therapy for high risk and recurrent prostate cancers is initially effective, but ultimately fails; better understanding the mechanisms should improve therapy. In two murine prostate cancer models, GR signaling is activated immediately following castration, substituting for the acute reduction in AR signaling, and allowing for continued tumor growth. This continued growth is blocked by relacorilant, selective GR antagonist in clinical trials for late-state PrCa. HighlightsO_LIAndrogen deprivation therapy induces regression of prostate cancer, but tumors recur C_LIO_LIMurine PrCa continues to proliferate for 3-14 days in two distinct mouse prostate cancer models C_LIO_LITumor cells proliferate during this period, and intratumoral glucocorticoids and glucocorticoid receptor (GR) protein increase, as does GR mRNA and a set of GR-regulated genes C_LIO_LIRelacorilant, a selective GR antagonist in clinical trials for late-state PrCa, eliminates the delayed regression C_LI

cancer biology↗

bioRxiv2021

TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease

Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNF-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNF and in vitro assays confirmed that TNF stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNF-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NF{kappa}B activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNF-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNF may mechanistically drive BPH via chronic activation of the signaling axis and NF{kappa}B. TNF blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. One sentence summaryPatient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.

cell biology↗