149 CALCIUM PROMOTES THE FORMATION OF BONE METASTASES VIA THE CALCIUM SENSING RECEPTOR IN PATIENTS WITH RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research I1 Apr 2012149 CALCIUM PROMOTES THE FORMATION OF BONE METASTASES VIA THE CALCIUM SENSING RECEPTOR IN PATIENTS WITH RENAL CELL CARCINOMA Elke Schneider, Frederik C. Roos, Christian Hampel, Joachim W. Thüroff, and Walburgis Brenner Elke SchneiderElke Schneider Mainz, Germany More articles by this author , Frederik C. RoosFrederik C. Roos Mainz, Germany More articles by this author , Christian HampelChristian Hampel Mainz, Germany More articles by this author , Joachim W. ThüroffJoachim W. Thüroff Mainz, Germany More articles by this author , and Walburgis BrennerWalburgis Brenner Mainz, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.199AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although a number of molecules have been implicated in the process of formation of cancer metastases, the organ-selective nature of cancer cells is still poorly understood. Renal cell carcinoma (RCC) often metastasize into bones, a calcium enriched tissue. We analyzed the influence of the calcium sensing receptor (CaSR) in RCC and an enhanced extracellular calcium concentration in processes of metastatic spread. METHODS In 33 matched RCC specimens, 11 non-metastasized, 11 metastasized into the lung and 11 metastasized into bones five years after nephrectomy, CaSR was quantified by RT-PCR and Western blot analyses. To investigate the influence of enhanced extracellular calcium on the formation of metastases, primary RCC cells were isolated from patients developing bone, lung and no metastasis five years after nephrectomy (each 3 cell lines). Cell proliferation after calcium treatment (2.5, 5 and 10 μM) was quantified by BrdU incorporation. Cell migration was determined in a Boyden chemotaxis assay with calcium as chemotactical agent (10 μM). Expression and activity of intracellular signal transduction mediators were analyzed by a human phospho kinase array and Western blot analyses. RESULTS Compared to non-metastasizing RCC, CaSR mRNA expression was 10.8-fold increased and CaSR protein level was 1.5-fold increased in tumor specimens of patients developing bone metastases. In primary RCC cells with a high bone metastastic potential CaSR expression was 3.7-fold higher compared to non-metastasizing RCC cells. Calcium treatment of bone-metastasizing RCC cells, but not of non-metastasizing cells, induced a concentration dependent enhancement of proliferation. In a Boyden chamber experiment with calcium as chemo attractant, RCC cells from patients with bone metastases showed a 9.4-fold higher migratory potential compared to cells from patients without metastases. In lung metastatic RCC cells migration was only 1.7-fold enhanced. The enhanced proliferation and migration of cells with high potential to build bone metastases seem to be caused by an activation of Akt and a highly increased integrin alpha 5 expression. Additionally, the tumor suppressor PTEN was markedly reduced in tumors metastasizing into bones and after calcium treatment, promoting tumor progression. CONCLUSIONS Our results indicate that formation of bone metastases of RCC is caused by an enhanced expression of the CaSR. Extracellular calcium has a promoting effect on cell migration and proliferation of bone metastasizing RCC cells via Akt signalling and integrin alpha 5. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e62 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elke Schneider Mainz, Germany More articles by this author Frederik C. Roos Mainz, Germany More articles by this author Christian Hampel Mainz, Germany More articles by this author Joachim W. Thüroff Mainz, Germany More articles by this author Walburgis Brenner Mainz, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...