EURURO Vol. 71 No. 5

776 844

Platinum Priority – Prostate Cancer
Editorial by Martijn Lolkema, Reno Debets and Ronald de Wit on pp. 788–789 of this issue
Subgroups of Castration-resistant Prostate Cancer Bone
Metastases Defined Through an Inverse Relationship Between
Androgen Receptor Activity and Immune Response
Erik Bovinder Ylitalo Elin Thysell Emma Jernberg Marie Lundholm Sead Crnalic
Lars Egevad Pa¨r Stattin Anders Widmark Anders Bergh Pernilla Wikstro¨m
a Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden; b Department of Surgery and Perioperative Sciences, Orthopedics, Umea
University, Umea, Sweden; c Section of Urology, Department of Surgical Science, Karolinska Institutet, Stockholm, Sweden; dDepartment of Surgery and
Perioperative Sciences, Urology & Andrology, Umea University, Umea, Sweden; e Department of Radiation Sciences, Oncology, Umea University, Umea,
Sweden
available at
journal homepage:
Article info
Article history:
Accepted July 19, 2016
Associate Editor:
Giacomo Novara
Keywords:
Bone metastasis
Castration-resistance
Immune response
Metabolism
Prostate cancer
Abstract
Background: Novel therapies for men with castration-resistant prostate cancer (CRPC)
are needed, particularly for cancers not driven by androgen receptor (AR) activation.
Objectives: To identify molecular subgroups of PC bone metastases of relevance for
therapy.
Design, setting, and participants: Fresh-frozen bone metastasis samples from men with
CRPC (n = 40), treatment-naı¨ve PC (n = 8), or other malignancies (n = 12) were charac-
terized using whole-genome expression profiling, multivariate principal component
analysis (PCA), and functional enrichment analysis. Expression profiles were verified by
reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone
metastases (n = 77) and compared to levels in malignant and adjacent benign prostate
tissue from patients with localized disease (n = 12). Selected proteins were evaluated
using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at trans-
urethral resection with long follow-up was used for prognostic evaluation.
Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-
driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1,
HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were
non–AR-driven. Functional enrichment analysis indicated high metabolic activity and
low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and
CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell
HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immuno-
reactivity. RT-PCR analysis showed lowMHC class I expression (HLA-A, TAP1, and PSMB9
mRNA) in PC bone metastases compared to benign and malignant prostate tissue and
bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity
was associated with high Gleason score, bone metastasis, and short cancer-specific
survival. Limitations include the limited number of patients studied and the single
metastasis sample studied per patient.
Conclusions: Most CRPC bonemetastases show high AR andmetabolic activities and low
immune responses. A subgroup instead shows low AR and metabolic activities, but high
immune responses. Targeted therapy for these groups should be explored.
* Corresponding author. Department of Medical Biosciences, Umea˚ University, 901 85 Umea˚ ,
Sweden. Tel. +46 90 7853752; Fax: +46 90 7852829.
E-mail address: (P. Wikstro¨m).
0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license ).