Treatment with ammonium tetrathiomolybdate inhibits the development of endometriotic-like lesions in TNFRp55-deficient mice

CONFORTI RA; DELSOUC MB; ZABALA AS; VALLCANERAS SS; MONTT-GUEVARA MM; GIANNINI A; SIMONCINI T; CASAIS M

Florencia

Congreso; Gynecological Endocrinology the 20th world congress; 2022

THE INTERNATIONAL SOCIETY OF GYNECOLOGICAL ENDOCRINOLOGY

Context: Endometriosis (EDT) is a chronic gynecological estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Different reports show altered levels of tumor necrosis factor-alpha (TNF-α) and its receptors TNFRp55 and TNFRp75 in patients. We show that EDT is exacerbated in TNFRp55-deficient mice. Studies in various cancers have shown that ammonium tetrathiomolybdate (TM, copper chelator) has anti-proliferative and anti-angiogenic effects. Similarly, we demonstrate that TM exerts the same effects on induced EDT in wild-type mice. Objective: We aimed to evaluate whether TM treatment affects the development of endometriotic-like lesions induced in TNFRp55-/- (KO) mice. Methods: Female C57BL/6 mice were divided into three groups: 1) KO Sham (placebo surgery), 2) KO EDT, and 3) KO EDT+TM. The EDT induction consisted of autologous uterine tissue transplantation to the intestinal mesentery. TM was administered orally (0.30 mg of TM/day/mouse) from postoperative day 15, and animals were euthanized one month after inducing pathology. Peritoneal fluid (PF) was collected for copper (Cu) determination by electrothermal atomic absorption spectrometry, estradiol by electrochemiluminescence, and TNF-α concentration by ELISA. Lesions were identified, counted, measured with a caliper in two perpendicular diameters for volume evaluation, and weighed. Then, the tissue was processed for the analysis of cell proliferation by PCNA immunohistochemistry and the mRNA expression of angiogenic markers and Tnfa by RT-qPCR. Results: We found that EDT increased Cu and estradiol levels in the PF of TNFRp55-/- mice compared to the KO Sham group, while the administration of TM restored the concentration of both factors. Besides, TM treatment reduced the weight and volume of lesions and the cell proliferation rate. Regarding angiogenesis, Cu chelation decreased the number of blood vessels and the mRNA expression of Vegf, Fgf2, and Pdgfb in lesions, compared to the KO EDT group. Furthermore, TM decreased the Tnfa expression in lesions and its concentration in PF. Conclusion: TM inhibits the EDT progression in TNFRp55-/- mice. Our results suggest the need to reposition this drug as a possible therapy for EDT in patients with the aberrant function of the TNF system.