Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys

HARO DURAND, LUIS; PONZIO, ROBERTO; PIGNATARO, OMAR PEDRO; ABIUSO, ADRIANA MARÍA BELÉN; BESIO MORENO, MARCOS; RIVAROLA, MARCO AURELIO; BERENSZTEIN, ESPERANZA; VARELA, MARÍA LUISA; MARCOS, ALEJANDRA; BELGOROSKY, ALICIA; MONDILLO, CAROLINA

EUROPEAN JOURNAL OF CANCER

ELSEVIER SCI LTD

Lugar: Amsterdam; Año: 2018 vol. 91 p. 125 - 135

0959-8049

Leydig cell tumors (LCTs) are rare steroid−secreting tumors of the testicular stroma, with apparent increased incidence. Symptoms include feminization or virilization in prepubertal boys, and erectile dysfunction, infertility and/or gynecomastia in adults. Although the etiology is unknown, multiple studies indicate that aromatase (CYP19) overexpression and excessive estrogen (E2) and IGF−1 production play a substantial role in Leydig cell tumorigenesis. LCTs are usually benign; however, malignant LCTs respond poorly to chemo/radiotherapy, highlighting the need to identify novel targets for treatment. Herein, we investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs in R2C rat Leydig tumor cells, a well−documented in vitro model for Leydigioma. Also, we studied for the first time the expression of CYP19, IGF-1R, ERα, ERβ, androgen receptor (AR) and HRH4 in human prepubertal LCTs versus normal prepubertal testes (NPTs). HRH4 agonist treatment inhibited steroidogenesis and proliferation in R2C cells, and also negatively affected their pro-angiogenic capacity in vitro and in vivo, as assessed by evaluating the proliferative activity of human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Moreover, E2 and IGF−1 inhibited HRH4 mRNA and protein levels. In human prepubertal LCTs, CYP19, IGF-1R, ERα and ERβ were overexpressed compared to NPTs. In contrast, HRH4 staining was weak in LCTs, but moderate/strong and confined to the interstitium in NPTs. Importantly, HRH4 was absent or barely detectable in seminiferous tubules or germ cells. Overall, our results point to HRH4 as a novel therapeutic target in LCTs.