INHIBIDORES DE HISTIDINA DECARBOXILASA ATENÚAN LA ACTIVIDAD PROANGIOGÉNICA DE CÉLULAS DE LEYDIG TUMORALES: ¿POTENCIAL TERAPIA NEOADYUVANTE PARA EL TRATAMIENTO DE LEYDIGIOMAS?

VARELA, MARÍA LUISA; PONZIO, ROBERTO; PIGNATARO, O.P.; HARO DURAND, LUIS; RIVAROLA, MARCO AURELIO; ABIUSO, ADRIANA MARÍA BELÉN; BERENSZTEIN, ESPERANZA; BESIO MORENO, M.; BELGOROSKY, ALICIA; MONDILLO, CAROLINA

REVISTA ARGENTINA DE ENDOCRINOLOGIA Y METABOLISMO

SOCIEDAD ARGENTINA DE ENDOCRINOLOGÍA Y METABOLISMO

Lugar: Buenos Aires; Año: 2018

0080-2077

Leydig Cell tumors (LCT) are a rare group of endocrine tumors in the testicular interstitium.Between 1 and 3% of testicular malignances in adults and 4% in prepubertal childrenbelong to LCT. An increasing incidence of this type of neoplasia has been reported recentlyall around the world. Particularly, a strong relationship between LCT and the use ofanabolic steroids (which are commonly used nowadays) has been reported recently. Inprepubertal boys, symptoms include feminization or virilization, depending on the majorcirculating steroid (estradiol or testosterone respectively). Adult patients show loss of libido,penile dysfunction, infertility and/or gynecomastia. Although the etiology still is unknown,several studies indicate that tumoral Leydig cells have an excessive production of insulinlike growth factor (IGF-1), as well as aromatase (CYP19) overexpression, which causes anenormous amount of estrogens (particularly estradiol, E2), and both factors play animportant role in tumorigenesis. While usually benign, when LCT became malignant inadults they respond poorly to radio and chemotherapy. Likewise, it has been reported thatboth therapies increase the incidence of several tumors. All these data imply the need ofnew therapeutic targets to avoid the chirurgical dissection of the testes and theconsequences of the hormonal therapies associated, which implicate not only the loss inreproductive function, but also psychological disorders. Several publications have reportedthat histidine decarboxylase (HDC), the only enzyme capable of catalyzing the conversionfrom L-histidine to histamine (HA) in mammals, has an important role in the development ofseveral types of tumors, such as colorectal, breast and melanoma. At the same time, in ourlaboratory we have reported that HA induces cell proliferation of murine Leydig cells, andcomplementary, this cell proliferation decreases when inhibiting selectively HDC, as well assteroid synthesis (progesterone and E2). Also, we observed a higher expression of HDC inpediatric LCT (n = 3) than normal controls corresponding to different stages of sexualmaturation (n = 9). It has been described that HDC knock out mice have an incompleteangiogenesis, and also that MA-10 Leydig cells HDC expression correlates with vascularendothelial growth factor (VEGF). The aim of this study is to improve our knowledge aboutthe role of HDC in LCT biology, particularly, the angiogenesis modulation. We used theR2C Leydig cell line, the most used model for in vitro studies of Leydigioma, because itoverexpresses CYP19 and constitutively produces high levels of IGF-1 and E2, as well ashuman LCT. R2C and pediatric LCT angiogenic capability was evaluated in vitro bymeasuring proliferation of human umbilical vein endothelial cells (HUVEC). In addition, we 4verified R2C cells angiogenic capability in vivo, using quail embryo vasculature(chorioallantoic membrane assay). Both models have been validated for the study ofangiogenesis. Conditioned medium obtained from R2C cell culture stimulated angiogenesisin vitro (p < 0.001) as well as in vivo (p < 0.001). The in vitro effect was reverted with aprevious treatment on the R2C cell culture using α-methyl-DL-histidine hydrochloride (αMHD, 10 µM), a specific HDC activity inhibitor (p < 0.001). Finally, human conditionedmedium from pediatric LCT increased HUVEC proliferation (p < 0.01). In the same way, theanalyzed patients showed higher testosterone and estradiol levels than normal serumconcentrations, which was in concordance to phenotypical features observed in presence ofLCT. Our results indicate that tumoral Leydig cells (TLC) produce HA, as well as otherangiogenic factors, and it could be stimulating the vascular endothelium. The selectiveinhibition of HDC attenuates the pro-angiogenic capability in TLC. Considering all theseresults and previous observations of our laboratory, specific inhibitors of HDC could beused, in the future, as a potential therapeutic target for the treatment of LCT.