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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between
Erik Bovinder Ylitalo1, Elin Thysell1, Emma Jernberg1
1Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
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-naïve PC (n=8), or other malignancies (n=12) were characterized 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 transurethral 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 immunoreactivity. RT-PCR analysis showed low MHC 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 bone metastases show high AR and metabolic 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.
Patient Summary:
We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.
Insights
Novel therapies are needed for castration-resistant prostate cancer (CRPC) not driven by androgen receptor (AR) activation. This study identified distinct molecular subgroups in CRPC bone metastases, suggesting tailored therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Castration-resistant prostate cancer (CRPC) requires novel therapeutic strategies, especially for tumors independent of androgen receptor (AR) signaling.
- Understanding molecular heterogeneity in CRPC bone metastases is crucial for developing targeted treatments.
Purpose of the Study:
- To identify and characterize molecular subgroups within prostate cancer (PC) bone metastases.
- To determine the relevance of these subgroups for guiding therapeutic decisions in CRPC.
Main Methods:
- Whole-genome expression profiling and principal component analysis (PCA) were performed on CRPC bone metastasis samples.
- Functional enrichment analysis, reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemistry were used for characterization.
- Prognostic evaluation was conducted on a cohort of PC patients with long follow-up.
Main Results:
- Eighty percent of CRPC bone metastases were AR-driven, exhibiting high AR and metabolic activity with low immune responses.
- Twenty percent were non-AR-driven, characterized by low AR and metabolic activity but high immune responses.
- Low MHC class I expression was observed in PC bone metastases, correlating with poor prognosis in primary PC.
Conclusions:
- CRPC bone metastases can be classified into AR-driven and non-AR-driven subgroups with distinct molecular and immune profiles.
- Targeted therapies should be explored for these specific subgroups to improve treatment outcomes.
- Molecular profiling of bone metastases may aid in selecting personalized therapies for prostate cancer patients.
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