Calcium-sensing Receptor (CaSR) Promotes Development of Bone Metastasis in Renal Cell Carcinoma

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 Apr 13

PMID 29644008

Citations 16

Authors

Sebastian Frees

Ines Breuksch

Tobias Haber

Heide-Katharina Bauer

Claudia Chavez-Munoz

Peter Raven

Igor Moskalev

Ninadh D Costa

Zheng Tan

Mads Daugaard

Joachim W Thuroff

Axel Haferkamp

Dirk Prawitt

Alan So

Walburgis Brenner

Affiliations

Soon will be listed here.

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 and . The RCC cell line 786-O was stably transfected with the 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 -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 -transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated 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.

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References

Guise T, Yin J, Mohammad K . Role of endothelin-1 in osteoblastic bone metastases. Cancer. 2003; 97(3 Suppl):779-84. DOI: 10.1002/cncr.11129. View

Hills C, Younis M, Bennett J, Siamantouras E, Liu K, Squires P . Calcium-sensing receptor activation increases cell-cell adhesion and β-cell function. Cell Physiol Biochem. 2012; 30(3):575-86. DOI: 10.1159/000341439. View

Yin J, Pollock C, Kelly K . Mechanisms of cancer metastasis to the bone. Cell Res. 2005; 15(1):57-62. DOI: 10.1038/sj.cr.7290266. View

Chirgwin J, Guise T . Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr. 2001; 10(2):159-78. View

Hannan F, Walls G, Babinsky V, Nesbit M, Kallay E, Hough T . The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). Endocrinology. 2015; 156(9):3114-21. PMC: 4541614. DOI: 10.1210/en.2015-1269. View

Jensen A, Brauner-Osborne H . Allosteric modulation of the calcium-sensing receptor. Curr Neuropharmacol. 2009; 5(3):180-6. PMC: 2656812. DOI: 10.2174/157015907781695982. View

Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Goto M . A novel molecular mechanism modulating osteoclast differentiation and function. Bone. 1999; 25(1):109-13. DOI: 10.1016/s8756-3282(99)00121-0. View

Saidak Z, Mentaverri R, Brown E . The role of the calcium-sensing receptor in the development and progression of cancer. Endocr Rev. 2009; 30(2):178-95. DOI: 10.1210/er.2008-0041. View

Gorvin C, Hannan F, Howles S, Babinsky V, Piret S, Rogers A . G mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI Insight. 2017; 2(3):e91103. PMC: 5291742. DOI: 10.1172/jci.insight.91103. View

10.

Chow W, Devesa S, Warren J, Fraumeni Jr J . Rising incidence of renal cell cancer in the United States. JAMA. 1999; 281(17):1628-31. DOI: 10.1001/jama.281.17.1628. View

11.

Canalis E . Novel treatments for osteoporosis. J Clin Invest. 2000; 106(2):177-9. PMC: 314318. DOI: 10.1172/JCI10584. View

12.

Ishibashi K, Haber T, Breuksch I, Gebhard S, Sugino T, Kubo H . Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade. Oncotarget. 2017; 8(33):55230-55245. PMC: 5589655. DOI: 10.18632/oncotarget.19420. View

13.

Nemeth E, Delmar E, Heaton W, Miller M, Lambert L, Conklin R . Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther. 2001; 299(1):323-31. View

14.

Hess K, Varadhachary G, Taylor S, Wei W, Raber M, Lenzi R . Metastatic patterns in adenocarcinoma. Cancer. 2006; 106(7):1624-33. DOI: 10.1002/cncr.21778. View

15.

Tharmalingam S, Daulat A, Antflick J, Ahmed S, Nemeth E, Angers S . Calcium-sensing receptor modulates cell adhesion and migration via integrins. J Biol Chem. 2011; 286(47):40922-33. PMC: 3220485. DOI: 10.1074/jbc.M111.265454. View

16.

Sun M, Choueiri T . Kidney cancer: Recurrence in renal cell carcinoma: the work is not done. Nat Rev Urol. 2016; 13(5):246-7. DOI: 10.1038/nrurol.2016.57. View

17.

DeCastro G, McKiernan J . Epidemiology, clinical staging, and presentation of renal cell carcinoma. Urol Clin North Am. 2008; 35(4):581-92. DOI: 10.1016/j.ucl.2008.07.005. View

18.

Haber T, Jockel E, Roos F, Junker K, Prawitt D, Hampel C . Bone Metastasis in Renal Cell Carcinoma is Preprogrammed in the Primary Tumor and Caused by AKT and Integrin α5 Signaling. J Urol. 2015; 194(2):539-46. DOI: 10.1016/j.juro.2015.01.079. View

19.

Rybczynska A, Marchwinska A, Dys A, Boblewski K, Lehmann A, Lewko B . Activity of the calcium-sensing receptor influences blood glucose and insulin levels in rats. Pharmacol Rep. 2017; 69(4):709-713. DOI: 10.1016/j.pharep.2017.01.034. View

20.

Mikami S, Oya M, Mizuno R, Kosaka T, Katsube K, Okada Y . Invasion and metastasis of renal cell carcinoma. Med Mol Morphol. 2013; 47(2):63-7. DOI: 10.1007/s00795-013-0064-6. View