High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor

The prognosis for renal cell carcinoma (RCC) is related to a high rate of metastasis, including 30% of bone metastasis. Characteristic for bone tissue is a high concentration of calcium ions. In this study, we show a promoting effect of an enhanced extracellular calcium concentration on mechanisms o...

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Bibliographic Details
Published in:Molecular cancer 2014-02, Vol.13 (1), p.42-42, Article 42
Main Authors: Joeckel, Elke, Haber, Tobias, Prawitt, Dirk, Junker, Kerstin, Hampel, Christian, Thüroff, Joachim W, Roos, Frederik C, Brenner, Walburgis
Format: Article
Language:English
Subjects:
Analysis
Blotting, Western
Bone and Bones - chemistry
Bone Neoplasms - secondary
Calcium
Calcium - metabolism
Carcinoma, Renal Cell - metabolism
Carcinoma, Renal Cell - secondary
Cell adhesion & migration
Cell culture
Cell growth
Complications and side effects
Development and progression
Endothelium
Flow Cytometry
Genetic aspects
Humans
Immunohistochemistry
Kidney Neoplasms - metabolism
Kidney Neoplasms - pathology
Kinases
Medical prognosis
Metastasis
Physiological aspects
Prognosis
Proteins
Receptors, Calcium-Sensing - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Risk factors
Software
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Summary:The prognosis for renal cell carcinoma (RCC) is related to a high rate of metastasis, including 30% of bone metastasis. Characteristic for bone tissue is a high concentration of calcium ions. In this study, we show a promoting effect of an enhanced extracellular calcium concentration on mechanisms of bone metastasis via the calcium-sensing receptor (CaSR) and its downstream signaling molecules. Our analyses were performed using 33 (11/category) matched specimens of normal and tumor tissue and 9 (3/category) primary cells derived from RCC patients of the 3 categories: non-metastasized, metastasized into the lung and metastasized into bones during a five-year period after nephrectomy. Expression of CaSR was determined by RT-PCR, Western blot analyses and flow cytometry, respectively. Cells were treated by calcium and the CaSR inhibitor NPS 2143. Cell migration was measured in a Boyden chamber with calcium (10 μM) as chemotaxin and proliferation by BrdU incorporation. The activity of intracellular signaling mediators was quantified by a phospho-kinase array and Western blot. The expression of CaSR was highest in specimens and cells of patients with bone metastases. Calcium treatment induced an increased migration (19-fold) and proliferation (2.3-fold) exclusively in RCC cells from patients with bone metastases. The CaSR inhibitor NPS 2143 elucidated the role of CaSR on the calcium-dependent effects. After treatment with calcium, the activity of AKT, PLCγ-1, p38α and JNK was clearly enhanced and PTEN expression was almost completely abolished in bone metastasizing RCC cells. Our results indicate a promoting effect of extracellular calcium on cell migration and proliferation of bone metastasizing RCC cells via highly expressed CaSR and its downstream signaling pathways. Consequently, CaSR may be regarded as a new prognostic marker predicting RCC bone metastasis.
ISSN:1476-4598
1476-4598
DOI:10.1186/1476-4598-13-42