SPECIFIC COMPONENTS OF THE HISTAMINERGIC SYSTEM AS POTENTIAL TARGETS FOR LEYDIG CELL TUMOR TREATMENT IN PREPUBERTAL BOYS

MONDILLO, CAROLINA

Mar del Plata

Congreso; Reunión Conjunta SAIC-SAI-SAFIS 2018; 2018

Sociedad Argentina de Investigación Clínica

Testicular Leydig cell tumors (LCTs) are rare neoplasms associated with endocrine dysfunctions in boys and adult men. Aromatase (CYP19) overexpression and excessive estrogen (E2) production are known to sustain Leydig cell tumorigenesis. Although mostly benign, LCTs can become malignant and unresponsive to current chemo/radiotherapy, highlighting the need to identify new therapeutic targets. Previously, we reported that L-histidine descarboxylase (HDC), responsible for histamine (HA) synthesis, is overexpressed in human prepubertal LCTs versus control prepubertal testes (CPTs), whereas HA receptor H4 (HRH4) is weakly expressed in these tumors compared to CPTs. Analogously, we observed that HA is an autocrine growth factor stimulating cell proliferation and steroid production through HA receptor H2 (HRH2) in mouse and rat Leydig tumor cells, while selective HRH4 activation decreases proliferation, steroidogenesis and angiogenesis. Recently, we assessed the effect of HDC inhibitors on Leydig tumor cell proliferative, steroidogenic and pro-angiogenic capacities. Experiments were performed in R2C rat Leydig tumor cells (R2C), the best-known in vitro model of Leydigioma. Cell proliferation was assessed using 3H-Thymidine and sulforhodamine B incorporation assays. CYP19 expression was evaluated by qPCR, and CYP19 activity was measured using a tritiated water-release assay. Steroid levels were determined by radioimmunoassay. The angiogenic potential of conditioned media from R2C and human Leydig tumor cells isolated from prepubertal LCTs (n=3) was evaluated in vitro and in vivo, using human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Our results show that HDC inhibitors can significantly diminish Leydig tumor cell proliferation (48-h), steroidogenesis (24-h) and angiogenesis (48-h). Also, we provide the first evidence that HA would be one of the pro-angiogenic factors secreted by Leydig tumor cells. Overall, our former and present results suggest that specifically targeting HDC and/or HRH4 may constitute a potential effective neoadjuvant therapy against LCTs, at least in prepubertal patients.