The Calcium-Sensing Receptor is A Marker and Potential Driver of Neuroendocrine Differentiation in Prostate Cancer.

Fanny Bery,Mathilde Cancel,Karine Mahéo,François Rozet,Roseline Guibon,Aurélie Chantôme,Franck Bruyère,Gaëlle Fromont

doi:10.3390/cancers12040860

Abstract

The mechanisms underlying neuroendocrine (NE) differentiation in prostate cancer (PCa) remain mostly uncharacterized. Since a deregulated calcium homeostasis has been reported in neuroendocrine prostate cancer (NEPC), we explored herein the link between NE differentiation and the calcium-sensing receptor (CaSR). CaSR expression was evaluated by immunohistochemistry—together with NE markers—on tissue microarrays containing samples of normal prostate, localized PCa, metastatic castration resistant PCa (MCRPC) and NEPC. In prostate tissues, we observed a strong association between CaSR and chromogranin expression. Both markers were strongly expressed in all cases of NEPC and co-expression was confirmed by double immunostaining. In MCRPC, the expression of CaSR was significantly associated with shorter overall survival. The involvement of CaSR in NE differentiation was evaluated in PCa cell lines. Inhibition of CaSR led to decrease the expression of neuronal (NSE, βtubulinIII) and NE (chromogranin, synaptophysin) markers in the NE PCa cell line NCI-H660. A decrease of neuronal and NE markers was also observed in siCaSR-transfected PC3 and 22RV1 cells, respectively, whereas CaSR activation increased both NSE and synaptophysin expression in PC3 cells. These results strongly suggest that CaSR is a marker and a driver of NE differentiation in PCa and emphasize the potential of CaSR directed therapy for NEPC patients.

Highlights

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and a common cause of male cancer death
Calcium-Sensing Receptor (CaSR) and chromogranin were expressed in the epithelial compartment in respectively 24 and 23 cases on 57, with less than 1% of positive cells (Figure 1A,B)
CaSR staining was observed on cancer cells in 26% of Clinically localized cancer samples (CLC) cases, 25% of metastatic castration resistant PCa (MCRPC) samples (Figure 1C) and 100% of neuroendocrine prostate cancer (NEPC) (Figure 1E)

Summary

Introduction

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and a common cause of male cancer death. Calcium (Ca2+ ) signaling has been involved in both the development and progression of PCa. Dietary calcium intake is associated with an increased risk of PCa and aggressive disease in several epidemiological studies [1,2,3,4]. Dietary calcium intake is associated with an increased risk of PCa and aggressive disease in several epidemiological studies [1,2,3,4] This is most likely linked to the fact that changes in cytosolic Ca2+ and Ca2+ signal trigger key events in cancer cells, such as proliferation, invasion and resistance to apoptosis [5]. Cancers 2020, 12, 860 such as excessive calcium intake in the diet, vitamin D deficiency, structural and functional changes in vitamin D receptor, changes in Ca2+ channels and Calcium-Sensing Receptor (CaSR) [6].

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Conclusion