Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives

Table 1 Examples of orthosteric agonists and allosteric modulators of the calcium-sensing receptor[13-15]

Ligand type	Class and examples	Reported effects on inflammation	Reported effects on cancer	Ref.
Orthosteric agonists	Inorganic divalent and trivalent cations: Zn2+ 1Ca2+; Mg2+; Gd3+	Reduces inflammation in mouse models of colitis	High Ca2+ intake: Associated low risk for CRC	[16-18]
		Intake is correlated with reduced inflammation
	Polyamines: Spermine spermidine, putrescine	Increase airway inflammation and hyperresponsiveness	Reduce pancreatic cancer growth in mice	[5,19]
	Aminoglycoside antibiotics: Neomycin, gentamycin, tobramycin	-	-
	Basic polypeptides: poly-l-arginine, 1poly-l-lysine, and amyloid β-peptides	Induces airway inflammation	-	[5,20]
		Reduces inflammation in mouse models of colitis
Combined orthosteric and allosteric modulators	D-amino-acid polypeptides: Etelcalcetide	-	-
	L-amino acids: Phenylalanine, tryptophan	-	-
	Glutamyl dipeptides: 1γ-Glu-Val, 1γ-Glu-Cys	Reduces inflammation in mouse models of colitis	-	[21]
Allosteric modulators (calcimimetics and calcilytics)	Small molecule calcimimetics: Sensipar (1Cinacalcet HCl), NPS-R568, GSK3004774	Increases airway hyperresponsiveness	Treatment of parathyroid tumours	[5,22-24]
			Inhibits neuroblastoma tumour growth
			Reduces hypercalcaemia of malignancy
	Small molecule calcilytics: 1NPS-2143, Calhex, Ronacalaret, AXT-914	Reduces pulmonary inflammation and airway hyperresponsiveness in rodents	-	[5,25,26]

¹Indicates the compounds for which the in vivo effects were reported. While many of these modulators have been reported to have in vitro effects on (cancer) cell lines, evidence of their in vivo activity has remained scarce. The table summarises their known (putatively) CaSR-mediated direct effects on inflammation and cancer in humans or animals. CRC: Colorectal cancer.

Table 2 Dual function of the calcium-sensing receptor as tumour suppressor and oncogene in various cancers and the affected calcium-sensing receptor-coupled signalling pathways

Cancer type	CaSR	Expression of the CaSR	Detection	Proposed signalling pathway	Ref.
Gastric	Oncogene	Increased	mRNA, protein	TRPV4	[49]
Prostate	Oncogene	Increased	mRNA, protein	PTHrP via trans-activation of the EGFR and ERK1/2 phosphorylation	[50-52]
				AKT phosphorylation
Breast	Oncogene	Increased in breast primary tumours and in bone metastases	mRNA, protein	PTHrP via cAMP	[53-57]
				ERK1/2 and TRPC1
				Inhibition of OPG via epiregulin
Renal carcinoma	Oncogene	Increased in bone metastasising tumours	mRNA, protein	AKT phosphorylation	[58]
Colorectal	Tumour suppressor	Reduced	mRNA, protein	Canonical and non-canonical Wnt/β-catenin pathway and EMT	[3,29,59-62]
Endometrial	Tumour suppressor	Reduced	Protein	Apoptosis	[63]
				Wnt/β-catenin
				VEGFR3
Parathyroid	Tumour suppressor	Reduced	mRNA, protein	Caveolin-1 and Gαq	[64-69]
				Cyclin D1 and RGS5
Neuro-blastoma	Tumour suppressor	Reduced	mRNA, protein	Apoptosis via ERK1/2	[22,70,71]
				Cancer testis antigens (CTAs)
Pancreatic	Unknown	Reduced	mRNA, protein	NCX1/Ca2+/ β-catenin	[19,72]