Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer.
Aged
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Inflammation
/ metabolism
Male
Middle Aged
Mitogen-Activated Protein Kinase 8
/ metabolism
Neoplasm Grading
Prognosis
Prostate
/ metabolism
Prostatic Neoplasms
/ metabolism
Receptors, Androgen
/ metabolism
Transcription Factors
/ metabolism
Tumor Microenvironment
T-lymphocytes
androgen receptor
inflammation
phosphorylation
prostate cancer
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
17
02
2020
revised:
21
07
2020
accepted:
04
08
2020
pubmed:
28
8
2020
medline:
14
1
2021
entrez:
27
8
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
PI3KCA protein, human
0
Receptors, Androgen
0
Transcription Factors
0
Mitogen-Activated Protein Kinase 8
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1353-1364Subventions
Organisme : Prostate Cancer UK
ID : S14-003
Pays : United Kingdom
Informations de copyright
© 2020 The Authors. The Prostate published by Wiley Periodicals LLC.
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