Calcium-sensing receptor in cancer: good cop or bad cop?

Abstract

The extracellular calcium-sensing receptor (CaR) is a versatile 'sensor' for di- and polycationic molecules in the body. CaR plays a key role in the defense against hypercalcemia by "sensing" extracellular calcium levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. Although mutation of CaR gene has so far not been associated with any malignancy, aberrant functions of CaR have implications in malignant progression. One situation is loss of CaR expression, resulting in loss of growth suppressing effects of elevated extracellular Ca(2+) by CaR, reported in parathyroid adenoma and in colon carcinoma. Another situation is activation of CaR, resulting in increased production of parathyroid hormone-related peptide (PTHrP), a primary causal factor in hypercalcemia of malignancy and a contributor to metastatic processes involving bone. CaR signaling and effects have been studied in several cancers including ovarian cancers, gastrinomas, and gliomas in addition to comparatively detailed studies in breast, prostate, and colon cancers. Studies on H-500 rat Leydig cells, a xenotransplantable model of humoral hypercalcemia of malignancy has shed much light on the mechanisms of CaR-induced cancer cell growth and survival. Pharmacological agonists and antagonists of CaR hold therapeutic promise depending on whether activation of CaR is required such as in case of colon cancer or inactivating the receptor is required as in the case of breast- and prostate tumors.

Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel

“…We found the two parameters to be negatively correlated (Fig. 1F), which is consistent with the notion that gastric cancer patients with hypercalcemia usually have poor prognosis (15)(16)(17). Because CaSR on the serosal side of gastric epithelial cells can be activated by serum calcium, we also analyzed the correlation between CaSR expression and survival of gastric cancer patients and found the patients with high CaSR expression showed markedly lower survival than those with low CaSR expression (Fig.…”

“…Therefore, we did not further compare the tumor growth in the mouse xenograft models with or without an intravenous injection of calcium. However, due to the facts that the gastric cancer cells with aberrant expression and function of CaSR are hypersensitive to [Ca 2þ ] o as shown presently and that gastric cancer patients usually develop hypercalcemia during their disease course as reported previously (15)(16)(17), any magnitudes of serum calcium rise may aggravate gastric cancer progression.…”

“…1E), indicating that a positive association of CaSR expression with gastric cancer progression. Because up to 30% of patients with cancers may develop hypercalcemia during their disease course (15)(16)(17), the correlation between serum calcium and the survival of gastric cancer patients was analyzed. We found the two parameters to be negatively correlated (Fig.…”

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…CaSR signaling has now been implicated in the development of several cancer types, including colon cancer, prostate cancer, breast cancer and lung cancer [99]. Whether the CaSR behaves as an oncogene or a tumor suppressor seems dependent on the tissue involved and/or the stage of disease (i.e.…”

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Recent reports clearly point to a role for the CaSR as a regulator of early development and as a guardian of the homeostatic balance between proliferation and differentiation in adults [19,68,70,71,73,75,89,92]. The identification of CaSR mutations that cause FHH and hypocalcemia [93][94][95][96][97][98], and the recent discoveries implicating the dysregulation of CaSR signaling in many other diseases [99,[113][114][115][119][120][121][122][123][124], position the CaSR as a broad therapeutic target. Adverse side-effects will likely be a challenging issue in the putative use of CaSR-modulating agents for the treatment of such a broad range of tissuespecific diseases; therefore, future studies should focus on the development of CaSR-modulating drugs with a higher selectivity for the CaSR and specificity for the tissue of interest.…”