Angiogenic mediators and Notch pathway components are associated with dopaminergic D2 receptors in human pituitary adenomas

SOFÍA PERRONE; AGUSTINA CHIMENTO; NADIA BONADEO; SOFIA VALLA; PENGYU TAO; GE CHEN; FENG LING; ARMANDO BASSO; ANDRÉS CERVIO; SILVIA BERNER; CAROLINA CRISTINA

Mar del Plata

Congreso; Reunión Conjunta de la Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Fisiología (SAFIS).; 2018

Pituitary adenomas (PA) account for the 25% of intracranial tumors. Dopaminergic agonists, as Cabergoline (CG), are the first line therapies for these tumors. CG through D2 receptor (D2R) reduces tumor volume and hormone secretion in prolactinomas and in other types of PA. However, some patients do not respond to CG and need radiation and/or surgery.Angiogenesis is essential for tumor growth and metastasis, but its relevance in pituitary tumors development is still controversial. Notch signaling is involved in angiogenesis regulation as in other cellular processes such as proliferation and cell renewal. In previous work, we demonstrated Notch pathway components expression in human pituitary adenomas and experimental models. In this work, we aimed to determine the association between angiogenesis, Notch pathway components and D2R in human PA. The expression of D2R, NOTCH2-3 receptors, the target gene HES1, the ligand JAGGED1 and the angiogenic markers VEGF, FGF2 and ENDOCAN were determined by RT-qPCR. Ki-67 proliferation index and α-SMA-based microvessel density were evaluated with immunohistochemistry. A strong positive correlation between D2R and VEGF was observed (R2=0,96; p=0,02; n=14). Furthermore, we found that VEGF also correlated with Notch target gene HES1 (p=0,03; n=11). The microvessel density and the vascular area in Non-functioning tumors were higher than in Functioning tumors; however, the vessel size was lower in Non-functioning. No correlation was found between the expression of the previously stated genes or α-SMA values with tumor proliferation index.Our results demonstrate an interaction between D2 receptor, angiogenesis and Notch signaling in pituitary adenomas and suggest that CG treatment response could be associated to the activation state of these pathways. Therefore, a combined approach consisting of CG and VEGF or Notch inhibitors could be more effective for resistant pituitary adenoma treatment.