Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer

Abstract

Background Tumor microenvironment inflammatory infiltration is proposed as a protumorigenic mechanism for prostate cancer with proinflammatory cytokines stimulating androgen receptor (AR) activity. However, association with patient prognosis remains unclear. This study derives an inflammatory gene signature associated with AR expression and investigates CD3+ and CD8+ T‐lymphocyte infiltration association with AR and prognosis. Methods Gene profiling of inflammatory related genes was performed on 71 prostate biopsies. Immunohistochemistry on 243 hormone‐naïve prostate cancers was performed for CD3, CD8, AR, and phosphorylated AR tumor expression. Results Multiple proinflammatory genes were differentially expressed in association with high AR expression compared with low AR expression including PI3KCA and MAKP8 (adjusted P < .05). High CD3+ and high CD8+ infiltration associated with reduced cancer‐specific survival (P = .018 and P = .020, respectively). High CD3+ infiltration correlated with high tumor cytoplasmic AR expression and if assessed together, they associated with reduced cancer‐specific and 5‐year survival from 90% to 56% (P = .000179). High CD8+ cytotoxic infiltration associated with high androgen‐independent tumor nuclear AR serine 213 phosphorylation (correlation coefficient = 0.227; P = .003) and when assessed together associated with poor clinico‐pathological features including perineural invasion (P = .001). Multiple genes involved in proinflammatory signaling pathways are upregulated in high AR expressing prostate samples. Conclusion T‐lymphocyte infiltration in hormone‐naïve disease associates with androgen‐independent driven disease and provides possible therapeutic targets to reduce transformation from hormone‐naïve to castrate‐resistant disease.

ANO1-downregulation induced by schisandrathera D: a novel therapeutic target for the treatment of prostate and oral cancers

“…In previous studies, we isolated thirteen dibenzocyclooctadiene lignans and neolignans, namely schisantherin B ( McAllister et al, 2020 ), tigloylgomisin P ( Butler and Huang, 2021 ), schirubrisin B ( Lee et al, 2018 ), schisantherin D ( Tai et al, 2011 ), (+)-deoxyschizandrin ( Liu et al, 2012b ), (+)-gomisin K3 ( Karakullukcu et al, 2011 ), angeloylgomisin H ( Sung et al, 2021 ), 3, 7-dihydroxy-1, 2, 13, 14-tetramethoxydibenzocyclooctadiene 12-O-β-D-glucopyranoside ( Vitório et al, 2020 ), schisandrathera B ( Jeong et al, 2022 ), meso-dihydroguaiaretic acid ( Galietta, 2022 ), schisandrathera D ( Seo et al, 2018 ), 4,4-bis(4-hydroxy-3-methoxyphenyl)-2,3-dimethyl-1-butanol ( Seo et al, 2016 ), and schisandrathera C ( Song et al, 2018 ), from the leaves of S. sphenanthera ( Figure 1 ). Their chemical structures, including absolute configurations were determined extensively by HR-ESI-MS, NMR, and ECD spectra and comparing their NMR data with that in reported literature ( Mai et al, 2021 ).…”

“…Prostate cancer is characterized by the expression of androgen receptors and prostate-specific antigen markers that have a considerable impact on its development. Therefore, hormone therapies for prostate cancer often target these markers ( McAllister et al, 2020 ). However, patients with prostatic small-cell neuroendocrine carcinoma frequently face restrictions in terms of their treatment, including hormone therapy ( Butler and Huang, 2021 ), since androgen receptors and prostate-specific antigen markers are not expressed in this type of cancer.…”

Peripheral Blood CD8+ T-Lymphocyte Subsets Are Associated with Prognosis in Prostate Cancer Patients

“…Previous studies have shown an association between the densities of CD8+ T lymphocytes in the peripheral blood and the prognosis of various types of cancers, including non-small cell lung, breast, colorectal, pancreatic and bladder cancers [10][11][12][13][14]. In prostate cancer (PCa), most studies have focused on the associations between intratumoral T lymphocyte subpopulations and clinical outcomes [15][16][17][18]. However, such analyses require prostatic tumor tissue, which is not always acquirable and, in many cases, the collected tissue material is not sufficient for exhaustive analyses.…”