Comprehensive analysis of androgen receptor status in prostate cancer with neuroendocrine differentiation

Ruopeng Su; Lei Chen; Zhou Jiang; Minghao Yu; Weiwei Zhang; Zehua Ma; Yiyi Ji; Kai Shen; Zhixiang Xin; Jun Qi; Wei Xue; Qi Wang

doi:10.3389/fonc.2022.955166

Comprehensive analysis of androgen receptor status in prostate cancer with neuroendocrine differentiation

Front Oncol. 2022 Aug 9:12:955166. doi: 10.3389/fonc.2022.955166. eCollection 2022.

Authors

Ruopeng Su¹, Lei Chen¹, Zhou Jiang², Minghao Yu³, Weiwei Zhang¹, Zehua Ma¹, Yiyi Ji¹, Kai Shen¹, Zhixiang Xin¹, Jun Qi³, Wei Xue¹, Qi Wang^{1

4}

Affiliations

¹ Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of AR^HIGH/NE^HIGH prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases (n = 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases (n = 153) showed AR positive and 19.0% (n = 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of AR^HIGH/NE^HIGH prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development.

Keywords: androgen receptor; immunohistochemistry; multiplex immunofluorescence; neuroendocrine differentiation; prostate cancer.