Benign prostatic hyperplasia (BPH) is a prevalent condition characterized by nonmalignant proliferation of epithelial and stromal components in the prostate, frequently resulting in lower urinary tract symptoms in aging men. While receptor tyrosine kinase (RTK) signaling has been implicated in both benign proliferative disorders and malignant tumors, its role in BPH remains insufficiently defined. In this study, transcriptomic analyses of bulk and single-cell RNA sequencing data revealed consistent activation of RTK signaling in prostatic epithelial cells from BPH tissues. Pharmacological inhibition of this pathway using sunitinib suppressed epithelial proliferation in BPH cell lines, organoid models, and an androgen-induced BPH mouse model. Through target screening, colony-stimulating factor 1 receptor (CSF1R) was identified as a central mediator within the RTK signaling cascade. Functional experiments demonstrated that CSF1R promotes epithelial proliferation through activation of the PI3K/AKT/mTOR pathway. Mechanistic studies further showed that fibroblasts, which are expanded in BPH tissues, secrete CSF1 and IL34, both ligands of CSF1R, thereby enhancing downstream signaling and stimulating epithelial growth. Neutralization of these ligands or silencing of CSF1R reversed fibroblast-induced epithelial proliferation and clonogenicity. Clinical observations in patients treated with sunitinib confirmed a significant reduction in prostate volume and improvement in BPH-related urinary symptoms. Collectively, these findings establish a fibroblast/CSF1R/RTK signaling axis that contributes to BPH pathogenesis and support the potential of RTK inhibition as a therapeutic strategy.
Molecular biomedicine. 2025 Nov 28*** epublish ***
Ming Zhan, Ruifeng Yang, Yue Gu, Jun Zhu, Miaomiao Guo, George Pupwe, Xiaohua Huang, Huan Xu, Zhilian Jia, Kyle Takehiro, Chong Liu, Bingyu Li, Yiwei Wang, Yanbo Chen, Xianjin Wang, Qi Chen, Bin Xu
Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China., Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China., Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China., Department of Pathology, City of Hope, Duarte, CA, 91010, USA., Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA, 91016, USA., Arcadia High School, Arcadia, CA, 91006, USA., Department of Pathology, Mount Sinai West/Morningside Hospitals, New York, NY, 10025, USA., Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. ., Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. ., Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. ., Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. .