Avaliação da sinalização purinérgica e inflamação crônica em pacientes após ressecção cirúrgica de PitNET

Abstract

Introduction: Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial tumors among endocrine neoplasms, with higher prevalence in women and individuals aged 30 to 40 years. Studies indicate that the purinergic system, together with tissue response to injury and inflammatory processes, are among the signaling pathways involved in the formation of the tumor microenvironment and in PitNET progression. Objective: To evaluate the activity, gene expression, and protein expression of the purinergic enzymes E-NTPDase (CD39) and Ecto-5’-nucleotidase (CD73), as well as serum levels of Interleukin-1β (IL-1β) in patients who underwent transsphenoidal surgery for the resection of PitNETs. Methodology: This is a cross-sectional study conducted in January 2024. Seventeen patients with a previous diagnosis of PitNET, who had undergone surgical resection 12 to 24 months prior to this research, were selected, along with 22 individuals in the control group. The activity and expression of the ectonucleotidases CD39 and CD73 in peripheral blood mononuclear cells (PBMCs) and platelets were assessed, in addition to extracellular ATP levels and serum IL-1β. Biological sample collection was carried out at the Regional Hospital, a reference center in western Santa Catarina, located in Chapecó, Brazil. For statistical analyses, data normality was verified using the Shapiro-Wilk test, followed by Student’s t-test, Mann-Whitney, and one-way ANOVA. A 95% significance level was adopted, and analyses were performed using GraphPad Prism 9.0.1. Results: In this study, the PitNET group (PG) presented a mean age of 57.78 years, with a predominance of females (66.7%) and hypertension as the most prevalent chronic disease (23.53%). Regarding tumor characteristics, macroadenomas (94.11%), PIT-1 cell lineage (35.3%), and gonadotroph tumors (23.52%) were more frequent. At the molecular and functional level, the PitNET group exhibited significantly increased levels of extracellular ATP (p = 0.0004) and serum IL-1β (p = 0.0017), indicating a persistent inflammatory environment. In addition, a reduction in CD39 activity in PBMCs was observed (p = 0.0039), associated with lower ATP hydrolysis capacity, contrasting with increased CD73 activity in platelets (p = 0.0096), which favors AMP hydrolysis and, consequently, the production of immunosuppressive adenosine. Furthermore, significant increases were found in CD39 protein expression (p < 0.0001), CD73 protein expression (p = 0.0013), and CD73 gene expression (p = 0.0349). Conclusion: The results demonstrated that PitNETs, even after surgical resection, promote persistent alterations in the activity and expression of purinergic enzymes, in addition to increasing serum IL-1β levels, contributing to a state of chronic inflammation and immunosuppression. These findings expand the understanding of PitNET pathophysiology and suggest that purinergic pathway components and inflammatory mediators may serve as prognostic biomarkers and potential therapeutic targets. The development of longitudinal studies is warranted to validate these biomarkers and guide novel strategies for the treatment and follow-up of affected patients.