HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Chattopadhyay, N. Search for Related Content PubMed PubMed Citation Articles by Chattopadhyay, N.

INVITED REVIEWS

Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy

Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts

The extracellular calcium-sensing receptor (CaR) plays a key role in the defense against hypercalcemia by "sensing" extracellular calcium (Ca²⁺_o) levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. However, CaR function can be aberrant in certain pathophysiological states, e.g., in some types of cancers known to produce humoral hypercalcemia of malignancy (HHM) in humans and animal models in which high Ca²⁺_o, via the CaR, produces a homeostatically inappropriate stimulation of parathyroid hormone-related peptide (PTHrP) secretion from these tumors. Increased levels of PTHrP set a cycle in motion whereby elevated systemic levels of Ca²⁺_o resulting from its increased bone-resorptive and positive renal calcium-reabsorbing effects give rise to hypercalcemia, which in turn begets worsening hypercalcemia by stimulating further release of PTHrP by the cancer cells. I review the relationship between CaR activation and PTHrP release in normal and tumor cells giving rise to HHM and/or malignant osteolysis and the actions of the receptor on key cellular events such as proliferation, angiogenesis, and apoptosis of cancer cells that will favor tumor growth and osseous metastasis. I also illustrate diverse signaling mechanisms underlying CaR-stimulated PTHrP secretion and other cellular events in tumor cells. Finally, I raise several necessary questions to demonstrate the roles of the receptor in promoting tumors and metastases that will enable consideration of the CaR as a potential antagonizing/neutralizing target for the treatment of HHM.

G protein-coupled receptor; osteolysis; metastasis; cytokine; receptor tyrosine kinase

This article has been cited by other articles:

				J. L. Gilmore, R. M. Gonterman, K. Menon, G. Lorch, D. J. Riese II, A. Robling, and J. Foley Reconstitution of Amphiregulin-Epidermal Growth Factor Receptor Signaling in Lung Squamous Cell Carcinomas Activates PTHrP Gene Expression and Contributes to Cancer-Mediated Diseases of the Bone Mol. Cancer Res., October 1, 2009; 7(10): 1714 - 1728. [Abstract] [Full Text] [PDF]

				L. A. Kingsley, P. G.J. Fournier, J. M. Chirgwin, and T. A. Guise Molecular Biology of Bone Metastasis Mol. Cancer Ther., October 1, 2007; 6(10): 2609 - 2617. [Abstract] [Full Text] [PDF]

				G. J. Strewler The Stem Cell Niche and Bone Metastasis IBMS BoneKEy, May 1, 2006; 3(5): 19 - 29. [Abstract] [Full Text] [PDF]