Dysregulation of Purinergic Signaling Sustains Chronic Inflammation and Oxidative Imbalance in Patients After PitNET Surgical Resection

Abstract

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial tumors. Evidence suggests that these types of tumors may have high recurrence rates. In this context, the purinergic system, oxidative stress, and inflammation are important signaling pathways involved in the cancer's pathophysiology. This study aimed to evaluate the sociodemographic and diagnostic profiles, as well as assess the purinergic signaling, immunological, and redox profiles, of patients after PitNET resection. We collected sociodemographic data and the patients' diagnostic profiles. We also collected blood samples to analyze glycemia, triglycerides, albumin, and ATP levels. The ectonucleotidase activity was determined in peripheral blood mononuclear cells (PBMCs). In addition, we evaluated their redox and immunological profiles. There was a prevalence of gonadotropic macroadenoma derived from PIT-1 cells. We found that patients included in the PitNET group had increased glycemia, serum ATP levels, and ATP hydrolysis in PBMCs. Analyzing their immunological profiles, we found that patients had increased levels of IL-6, IL-10, and TNF, while the IL-27 level was decreased. Regarding their redox profiles, PitNET patients had increased levels of ROS and protein carbonylation. Unexpectedly, patients also showed increased levels of non-protein thiols (NPSHs), total thiols (PSHs), and ascorbic acid. Thus, the dysregulation of purinergic signaling sustained chronic inflammation and oxidative imbalance in PitNET patients for a long time after surgical resection. These data suggest that patients with PitNETs require long-term accompanying to prevent cancer recurrence prognosis. The biomarkers highlighted in this study may be good tools to help the medical approaches.

Keywords: ectonucleotidases; inflammation; neuroendocrine tumor; oxidative stress; purinergic signaling; surgical resection.

Figure 1

The levels of biochemical markers. In comparison with the controls, patients in the PitNET group presented increased glycemia (A), while there was no statistical significance for the levels of triglycerides (B) and albumin (C). Statistical analysis: Student’s t-test or the Mann–Whitney test was used to compare the groups. p < 0.05 was considered statistically significant. * (p < 0.05).

Figure 2

Extracellular ATP (eATP) levels and ectonucleotidases activity in PBMCs. We found that the PitNET group had significantly increased levels of ATP in serum (eATP) in comparison with the control group (A). Regarding the ectonucleotidase activity, we found an increased hydrolysis of ATP (B), while there was no statistical significance for hydrolysis of ADP (C) and AMP (D). Statistical analysis: Student’s t-test or the Mann–Whitney test was used to compare the groups. p < 0.05 was considered statistically significant. ** (p < 0.01); *** (p < 0.001).

Figure 3

Immunological profiles. The levels of IL-2 (A), IL-4 (B), and IFN-γ (G) were unchanged, while IL-6 (C), IL-10 (D), and TNF (F) were increased in patients with PitNETs. In the case of IL-27, levels were reduced in the PitNET group (E). Statistical analysis: Student’s t-test or the Mann–Whitney test was used to compare the groups. p < 0.05 was considered statistically significant. * (p < 0.05); **** (p < 0.0001).

Figure 4

Redox profiles. We discovered that patients from the PitNET group had a redox imbalance, with increased levels of ROS (A) and protein carbonylation (D). In contrast, we also verified an increase in the levels of NPSH (E), PSH (F), and ascorbic acid (G) in the PitNET group. We did not find any statistical significance for the levels of MPO (B), TBARS (C), and SOD (H). Statistical analysis: Student’s t-test or the Mann–Whitney test was used to compare the groups. p < 0.05 was considered statistically significant. * (p < 0.05); *** (p < 0.001); **** (p < 0.0001).