Over-expression of vascular endothelial growth factor in pituitary adenomas is associated with extrasellar growth and recurrence

Abstract

Some pituitary adenomas (PA) demonstrate aggressive behavior with local invasion and recurrences. Angiogenesis is regarded as an essential step in the formation of solid tumors. The aim of this study is to find out whether angiogenic factors may have information about the aggressiveness of PA that could be useful in determining the frequency of follow-up and whether adjuvant therapy is necessary. In this retrospective descriptive study, we evaluated vascular endothelial growth factors (VEGF) and VEGF receptor (KDR) mRNA expression by RT-PCR analysis on 46 human PA samples. Clinical data, histological subtype and radiologic characteristics were studied to determine the associations between the variables and the pre-operative behavior of the tumor. In addition, we monitored 12 patients without adjuvant post-operative therapies over 46 months after surgery, determining progression of tumor remnants and its association with these markers. VEGF expression correlates with KDR expression (r = 0.40, p = 0.006). VEGF demonstrates different expression between histological subtypes (p = 0.036). The extension at magnetic resonance imaging showed that VEGF expression was related to suprasellar extension (p = 0.007), being expressed more on tumors with extrasellar growth than intrasellar ones (p = 0.008). Our results demonstrate a 27.5 times increased risk of extrasellar growth when VEGF expression exceeds 0.222 normalized copy number (NCN) (p = 0.002). Likewise, tumors with KDR greater than 0.750 NCN had less recurrence-free survival time (p = 0.032). Our results suggest that the expression of VEGF and its receptor could be a marker for poor outcome after partial tumor resection. These data should be considered in future studies evaluating angiogenic factors as therapeutic targets in patients with PA.

Markery Proliferacji I Inwazyjności W Guzach Przysadki Wydzielających Hormon Wzrostu

“…A low AIP score was found in large somatotropinomas [33]. No correlation of VEGF expression with tumour size was stated [29,31], which our study confirms.…”

“…Higher VEGF expression was seen in invasive non-functioning giant adenomas and tumours with extrasellar growth [25,29], in contrast to low VEGF expression in patients, 70% of whom achieved remission [35]. We may thus presume that VEGF plays an indirect role in the development of somatotropinomas, being an independent stimulator of angiogenic growth and progression in GH-secreting adenomas.…”

“…On the other hand, in a RT-PCR study of different subtypes of pituitary adenomas, somatotropinomas showed lowest VEGF expression [29,30]. In IHC, expression of VEGF was decreased in somatotropinomas, against normal tissue [31].…”

“…In patients with invasive adenomas pre-treated with SSA before surgery, a decrease in VEGF staining was observed [28,31,36], as well as lower expression of VEGF mRNA [29], suggesting that SSA may inhibit angiogenesis through down-regulation of VEGF. However, studies on SSA modulation of VEGF expression are few and inconclusive [29].…”

Gene therapy in endocrine tumors: A comprehensive overview [Review]

“…Recently, vascular endothelial growth factor (VEGF), its receptor VEGFR, and angiogenic factors were examined in 46 human pituitary adenomas, and the results supported the conclusion that VEGF and its receptor could serve as markers of poor outcome after partial tumor resection [25]. Therefore, gene therapy performed using antisense cDNAs that target bFGF, EGF, VEGF,or their receptors may be an effective approach, and this has been used in treating brain tumorsin animal models [17].…”