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.
Highlights
Renal cell carcinoma (RCC) is among the ten most common cancer sites in men and women
Calcium induced an increase in cell adhesion, migration and proliferation of calcium-sensing receptor (CaSR)-transfected 786-O cells in vitro
The CaSR inhibitor NPS2143 revised the described cellular effects, demonstrating its CaSR dependence. These results show that in our cell system calcium, via CaSR, induces enhanced metastatic behavior of renal cell carcinoma (RCC) cells leading to the development of bone metastasis
Summary
Renal cell carcinoma (RCC) is among the ten most common cancer sites in men and women. Current estimates show that 62700 new cases will occur in the United States in 2016 and 14420 patients will die of their disease [1]. About 10% of all patients diagnosed with. RCC have metastasis at presentation and another 20–30% of patients will develop metastasis despite an initially curative treatment approach [4]. The most common sites of metastasis in RCC include lung (60%), bone (35%) liver (20%) and brain (10%) [5, 6]. Bone metastasis include rib and pelvis (50%) as well as spine (40%), often leading to significant pain in patients and decrease in quality of life [7]. Limiting bone metastasis in patients with advanced renal cell carcinoma is a crucial treatment goal
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