Calcium-sensing receptor (CaSR) promotes development of bone metastasis in renal cell carcinoma

// Sebastian Frees 1, 2, * , Ines Breuksch 3, * , Tobias Haber 2 , Heide-Katharina Bauer 3 , Claudia Chavez-Munoz 1 , Peter Raven 1 , Igor Moskalev 1 , Ninadh D´Costa 1 , Zheng Tan 1 , Mads Daugaard 1 , Joachim W. Thuroff 2, 4 , Axel Haferkamp 2 , Dirk Prawitt 5 , Alan So 1 and Walburgis Brenner 2, 3 1 Department of Urologic Sciences, University of British Columbia, Vancouver Prostate Centre, British Columbia, Canada 2 Department of Urology, Johannes Gutenberg University Medical Center, Mainz, Germany 3 Department of Gynecology, Johannes Gutenberg University Medical Center, Mainz, Germany 4 Current address: Department of Urology, University Clinic Mannheim, Mannheim, Germany 5 Department of Pediatrics, Johannes Gutenberg University Medical Center, Mainz, Germany * These authors contributed equally to this work Correspondence to: Sebastian Frees, email: sebastian.frees@unimedizin-mainz.de Keywords: renal cell carcinoma; calcium-sensing receptor; bone metastases, metastasis; kidney cancer Received: December 21, 2017      Accepted: February 25, 2018      Epub: March 02, 2018      Published: March 20, 2018 ABSTRACT Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo . The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR -transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR -transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.