Benign Prostatic Hyperplasia (BPH) is a common condition marked by the enlargement of the prostate gland, which often leads to significant urinary symptoms and a decreased quality of life. The development of clinically relevant animal models is crucial for understanding the pathophysiology of BPH and improving treatment options. This study aims to establish a patient-derived xenograft (PDX) model using benign prostatic tissues to explore the molecular and cellular mechanisms of BPH. PDXs were generated by implanting fresh BPH (transition zone) and paired normal (peripheral zone) prostate tissue from eight patients under the renal capsule of immunodeficient male mice. Tissue weight, architecture, cellular proliferation, apoptosis, prostate-specific marker expression, and molecular profiles of PDXs were assessed after 1 week, 1 month, 2 months, or 3 months of implantation by immunohistochemistry, ELISA, transcriptomics, and proteomics. Responses to finasteride, a standard-of-care therapy, were evaluated. PDXs maintained the histological and molecular characteristics of the parental human tissues. BPH, but not normal PDXs, demonstrated significant increases in weight and cellular proliferation, particularly at 1 month. Molecular profiling revealed specific gene and protein expression patterns correlating with BPH pathophysiology. Specifically, an increased immune and stress response was observed at 1 week, followed by increased expression of proliferation markers and BPH-specific stromal signaling molecules, such as BMP5 and CXCL13, at 1 month. Graft stabilization to pre-implant characteristics was apparent between 2 and 3 months. Treatment with finasteride reduced proliferation, increased apoptosis, and induced morphological changes consistent with therapeutic responses observed in human BPH. Our PDX model recapitulates the morphological, histological, and molecular features of human BPH, offering a significant advancement in modeling the complex interactions of cell types in BPH microenvironments. These PDXs respond to therapeutic intervention as expected, providing a valuable tool for preclinical testing of new therapeutics which will improve the well-being for BPH patients.
Laboratory investigation; a journal of technical methods and pathology. 2024 Aug 31 [Epub ahead of print]
Alexandra L Polasko, Dalin Zhang, Avanti Ramraj, Chun-Lung Chiu, Fernando J Garcia-Marques, Abel Bermudez, Kathryn Kapp, Eric Peterson, Zhengyuan Qiu, Anna S Pollack, Hongjuan Zhao, Jonathan R Pollack, Sharon J Pitteri, James D Brooks
Department of Urology, Stanford University, Stanford, CA 94305, USA., Department of Radiology, Stanford University, Stanford, CA 94305, USA; Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA 94305, USA., Department of Pathology, Stanford University, Stanford, CA 94305, USA., Department of Urology, Stanford University, Stanford, CA 94305, USA; Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA 94305, USA. Electronic address: .