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Abstract B076: Osteoclasts influence androgen-related gene expression in prostate cancer cells

Background: The majority of progressive prostate cancer will develop metastases in the skeleton. In bone environment, the regulated destruction of bone matrix by osteoclasts is closely connected to the formation of new bone by osteoblasts. Although prostate cancer often forms sclerotic bone lesions, evidence from recent research show that prostate cancer cells also produce factors to promote osteoclastic action. However, little is known on how osteoclasts regulate the prostate cancer growth in bone. The aim of the present study was to investigate the role of osteoclasts in the crosstalk of bone microenvironment and prostate cancer cells. Methods: The interactions between prostate cancer cells and osteoclasts were studied in a coculture model using the transwell permeable supports system. Two castration-resistant prostate cancer cell lines (LNCaP-19 and PC3) were used together with osteoclasts that were transformed from the RAW 264.7 cells by stimulation with RANKL. After 48 hours coculturing, analysis on gene expression level was carried out with qRT-PCR. Results: The results show that osteoclasst directly influence gene expression patterns in prostate cancer cells, affecting genes generally involved in tumor progression, mainly in the osteolytic cell line PC3. In LNCaP-19 cells, which are sensitive to androgens, osteoclast stimulation upregulated expression of androgen receptor (AR), as well as the AR splice-variant ARV7. In contrast, in androgen-insensitive PC3 cells no such changes in AR and AR-V7 mRNA were detected. Instead, the expression of the steroidogenic enzymes CYP11A1 (converting cholesterol into pregnenolone) and CYP19A1 (converting testosterone into estrogen) were increased by osteoclast stimulation. In addition, osteoclast stimulation differentially affects expression of genes related to bone formation in the tumor cells. LNCaP-19, which gives osteoblastic lesions in mouse tibia, responds with increased expression of genes related to TGF-b signaling, osteogenesis, and bone matrix formation. In contrast, the osteolytic cell line PC3 downregulates expression of osteogenic genes in response to osteoclast stimulation. Conclusion: This study shows that there is a direct crosstalk between osteoclasts and prostate cancer cells, where the osteoclasts influence gene expression related to androgen signaling, steroidogenesis, and osteogenesis in different ways based on the androgen and bone-related characteristics of the prostate cancer cells. Since upregulated AR and induced ARV7 expression have been shown to assist the progression of castration-resistant prostate cancer cells, inhibiting this crosstalk by targeting osteoclasts may improve efficacy of androgen-targeting drugs. Citation Format: Junchi Huang, Jan-Erik Damber, Karin Welen. Osteoclasts influence androgen-related gene expression in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B076.