Abstract
Pituitary apoplexy is a clinical syndrome with unknown pathogenesis. Therefore, identifying the underlying mechanisms is of high clinical relevance. Tumor necrosis factor alpha (TNF-α) is a critical cytokine mediating various hemorrhagic events, but little is known about its involvement in pituitary apoplexy. Here we show that TNF-α may be an important regulator of hemorrhagic transformation in pituitary adenomas. In this study, sixty surgical specimens of hemorrhagic and non-hemorrhagic human pituitary adenomas were examined. Hemorrhagic pituitary adenomas displayed higher protein and mRNA levels of TNF-α, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) compared with those of non-hemorrhagic tumors. Exposure of MMQ pituitary adenoma cells to TNF-α induced VEGF and MMP-9 expression in vitro. Additionally, TNF-α administration caused hemorrhagic transformation and enhanced VEGF and MMP-9 expression in MMQ pituitary adenoma cell xenografts in mice. Blockers of VEGF or MMP-9, either alone or in combination, attenuated but not abrogated TNF-α mediated hemorrhagic transformation in xenografts. This study suggests that TNF-α may play a role in the development of intratumoral hemorrhage in pituitary adenomas via up-regulation of VEGF and MMP-9.
Highlights
Pituitary apoplexy is a potentially life-threatening syndrome resulting from hemorrhage, hemorrhagic infarction or infarction of a pre-existing pituitary adenoma [1]
This study suggests that TNF-α may play a role in the development of intratumoral hemorrhage in pituitary adenomas via up-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9)
The results indicate that VEGF or MMP-9 inhibitors, either alone or in combination, could attenuate TNF-α mediated hemorrhagic transformation in MMQ cell xenograft tumors
Summary
Pituitary apoplexy is a potentially life-threatening syndrome resulting from hemorrhage, hemorrhagic infarction or infarction of a pre-existing pituitary adenoma [1]. The reported incidence of apoplectic pituitary tumors varies from 0.6 to 10% of all surgically resected adenomas [2]. Pathological studies show that more than 60% of apoplectic pituitary adenomas display hemorrhage or hemorrhagic infarction [3]. The mechanisms underlying hemorrhagic transformation in pituitary adenomas remain unclear. Increasing evidence from recent studies suggests that TNF-α plays a critical role in the development of various hemorrhagic events [4,5,6]. TNF-α is a well-known cytokine involved in multiple pathological processes such as angiogenesis, destruction of vascular integrity, and vascular hyperpermeability [7], which promote hemorrhagic transformation [6]
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