Background: The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients, suggests that up-regulated intracrine steroidogenesis might contribute to tumour growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoural steroidogenesis of castration resistant prostate cancer (CRPC) in bone.
Methods: To determine the role of osteoblasts in intratumoural steroidogenesis of CRPC, we accessed the effect of osteoblast conditioned medium (OCM) on the expression of steroidogenic enzymes in androgen-dependent LNCaP, osteogenic LNCaP-19 and osteolytic PC-3 cells using qPCR. Immunohistochemistry was used to detect changes on the protein level in tissue specimens from intratibial, subcutaneous and orthotopic LNCaP-19 xenograft tumours. Serum levels of OPG and RANKL was measured by ELISA.
Results: Osteoblasts induce and alter the steroidogenic transcription program in CRPC cells closely mimicking the gene expression pattern described in bone metastatic tissue from patients. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), oestrogen signalling-related genes (CYP19A1, and ERβ), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15 and UGT2B17). The altered steroid enzymatic pattern was bone specific and verified exclusively in tissue specimens from intratibial LNCaP-19 xenograft tumours. Additionally, serum levels of bone-produced OPG and RANKL reflected an increased oestrogen response in vivo.
Conclusions: Our results demonstrate that osteoblasts are important mediators of the intratumoural steroidogenesis of CRPC and for castration-resistant growth in bone and therefore need to be taken into consideration in the development of new therapeutic approaches.
Disclosure: The authors declared no competing interests. This study was supported by grants from the Swedish Cancer Society: CAN2011/534, ALF/Västra, Sahlgrenska University Hospital Götalandsregionen: ALFGBG-138351, Hillevi Fries, Percy Falks Foundation for Prostate and Breast Cancer Research, Proliv Väst, and Assar Gabrielssons Foundations for Clinical Research: FB12-55 & FB13-81.