Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression

Ahearn, Thomas U.; Tchrakian, Nairi; Wilson, Kathryn M.; Lis, Rosina T.; Nuttall, Elizabeth; Sesso, Howard D.; Loda, Massimo; Giovannucci, Edward; Mucci, Lorelei A.; Finn, Stephen P.; Shui, Irene M.

doi:10.1210/jc.2016-1082

Cited by 33 publications

(31 citation statements)

References 38 publications

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“…Therefore, loss of the receptor, as seen in colorectal or parathyroid tumours, confers malignant potential, suggestive of a tumour suppressor role. In contrast, in prostate and breast tumours, expression of CaSR is increased, and it seems that it favours metastasis to the bone, acting as an oncogene [55, 56]. Normal and neoplastic mammary epithelial cells express CaSR.…”

Section: Calcium-sensing Receptor and Other Diseasesmentioning

confidence: 99%

Diseases associated with calcium-sensing receptor

Vahé

Benomar

Espiard

et al. 2017

Orphanet J Rare Dis

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The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter’s syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

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Section: Calcium-sensing Receptor and Other Diseasesmentioning

confidence: 99%

Diseases associated with calcium-sensing receptor

Vahé

Benomar

Espiard

et al. 2017

Orphanet J Rare Dis

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“…CASR expression was observed predominantly in the cytoplasm and membrane of colorectal carcinoma cells, but occasionally in the nucleus of tumor cells. Consistent with the previous report, we evaluated the intensity of cytoplasmic/membrane stain for scoring. We observed CASR expression in many types of cells, including colorectal normal epithelial cells, immune cells, endothelial cells, smooth muscle cells and ganglion cells.…”

Section: Methodsmentioning

confidence: 87%

“…Also, CASR has pleiotropic effects and can regulate gene expression, inflammation, cell proliferation, cell differentiation and apoptosis . Deregulation of CASR has been implicated in different types of benign or malignant tumors of prostate, breast, parathyroid and colon …”

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confidence: 99%

“…[3][4][5] Deregulation of CASR has been implicated in different types of benign or malignant tumors of prostate, breast, parathyroid and colon. 3,[6][7][8][9][10][11] Although the underlying mechanisms are not completely understood, higher calcium intake was associated with a lower risk of colorectal cancer in most epidemiological studies. 12,13 Experimental studies reported a possible role of CASR in inhibiting proliferation of colonic epithelia.…”

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Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

Momen-Heravi

Masugi

Qian

et al. 2017

Intl Journal of Cancer

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Although experimental evidence suggests calcium-sensing receptor (CASR) as a tumor-suppressor, the prognostic role of tumor CASR expression in colorectal carcinoma remains unclear. We hypothesized that higher tumor CASR expression might be associated with improved survival among colorectal cancer patients. We evaluated tumor expression levels of CASR by immunohistochemistry in 809 incident colorectal cancer patients within the Nurses’ Health Study and the Health Professionals Follow-up Study. We used Cox proportional hazards regression models to estimate multivariable hazard ratio (HR) for the association of tumor CASR expression with colorectal cancer-specific and all-cause mortality. We adjusted for potential confounders including tumor biomarkers such as microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, expressions of PTGS2, VDR, and CTNNB1, and mutations of KRAS, BRAF, and PIK3CA. There were 240 colorectal cancer-specific deaths and 427 all-cause deaths. The median follow-up of censored patients was 10.8 years (interquartile range: 7.2, 15.1). Compared to patients with no or weak expression of CASR, the multivariable HRs for colorectal cancer-specific mortality were 0.80 [95% confidence interval (CI): 0.55-1.16] in patients with moderate CASR expression, and 0.50 (95% CI: 0.32-0.79) in patients with intense CASR expression (p-trend = 0.003). The corresponding HRs for overall mortality were 0.85 (0.64-1.13) and 0.81 (0.58-1.12), respectively. Higher tumor CASR expression was associated with a lower risk of colorectal cancer-specific mortality. This finding needs further confirmation and if confirmed, may lead to better understanding of the role of CASR in colorectal cancer progression.

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“…In clinical trials with healthy individuals the most common adverse effects of [ 5 1 _ T D $ D I F F ] calcilytics were mild disorders of the gastrointestinal tract and nervous system, such as fatigue, headache, constipation, diarrhea, nausea, and dyspepsia [76,81], which might be related to CaSR expressed in gut [82] and brain [83]. CaSR is also present in skin, lung, heart, mammary glands, and numerous other tissues [18,[84][85][86], but the physiological and pharmacological significance of CaSR expression in these tissues has been disputed [87]. Potential short-and long-term adverse effects of calcilytics cannot be ruled out, and will need to be evaluated in clinical studies before calcilytics can be used for routine medical treatment of ADH and BS5 patients.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics

Mayr

Glaudo

Schöfl

2016

Trends in Endocrinology & Metabolism

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Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression

Abstract: Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.

Cited by 33 publications

References 38 publications

Diseases associated with calcium-sensing receptor

Diseases associated with calcium-sensing receptor

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics

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