Endocrine Abstracts

More than 90% of malignant testicular tumors arise in the germ cells and are denoted testicular germ cell tumors (TGCTs). TGCTs are one of the most common cancers among men between 15 to 40 years of age and arise from a common precursor cell, the germ cell neoplasia in situ (GCNIS), an arrested and transformed fetal gonocyte that become invasive after puberty. TGCTs are divided into seminomas and nonseminomas based on histology. Fortunately, TGTCs are highly sensitive to cisplatin-based chemotherapy and therefore the survival rate is high. However, adverse effects involve an increased risk of infertility and other comorbidities, highlighting the importance of chemotherapy-reducing strategies. The calcium sensing receptor (CaSR) is a key player in the regulation of calcium homeostasis, exerting its primary function in the parathyroid gland and the kidneys. CaSR has been implicated in the pathogenesis of various cancers including colorectal- and breast cancer, exerting both oncogenic- and tumor suppressor functions. However, the role of CaSR in TGCTs have not previously been described. CaSR can be targeted using the negative allosteric modulator, NPS-2143, and the FDA-approved positive modulator, Cinacalcet. Therefore, we investigated the influence of CaSR in TGCTs as a potential target for chemotherapy-reducing treatment. The expression of CaSR was investigated by qPCR, western blot, and immunohistochemistry (IHC) in TGCT cell lines and human samples of normal testis, GCNIS, and TGCTs. The effect of treatment of TGCT-derived cell lines with Cinacalcet, NPS-2143, or calcium was assessed in vitro using proliferation assays. Finally, the effect of positive allosteric modulation of CaSR using Cinacalcet was determined in vivo using TGCT xenograft mouse models. CaSR was expressed in normal testis, GCNIS, TGCTs, and TGCT cell lines. mRNA levels of CaSR were correlated with markers of pluripotency, NANOQ and Oct-4. Additionally, expression levels of CaSR were strongly correlated with PTHrP in GCNIS and embryonal carcinoma tissue suggesting a link between these two factors. Western blot and IHC demonstrated expression of CaSR in normal testis, GCNIS, and TGCTs. In vitro experiments revealed a slight increase in proliferation of embryonal carcinoma-derived NTera2 cells treated with cinacalcet and a corresponding decreased proliferation when treated with NPS-2143. Accordingly, treatment with Cinacalcet increased tumor volume in an NTera2 xenograft mouse model. This study indicates potential growth regulating effects of CaSR in TGCTs and suggests that cellular calcium homeostasis in TGCTs may be a promising target for developing novel chemotherapy-reducing strategies.