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• W89726717 abstract "Background. The most frequent adrenocortical tumors (ACT) are benign forms defined as adrenocortical adenomas (ACA) with an estimated incidence of about 7.3%. Malignant forms, adrenocortical carcinomas (ACC) are rare endocrine tumors with poor prognosis and incidence of 1-2 cases per million people in the population. Currenlty ACC treatments are ineffective and substantially are based on the use of mitotane (o,p'DDD) with or without traditional chemotherapeutic agents. Because of dissimilar prognosis of ACA or ACC it is important to differentiate these two forms.Many tumors stimulate the growth of blood vessels by the angiogenesis process. Recently, vascular endothelial growth factor (VEGF) over-expression in ACC and VEGF receptors (VEGFR-1 and VEGFR-2) expression were found on tumor cells; these findings suggest a possible autocrine effect of VEGF for cell growth.Sorafenib, a multikinase inhibitor, inhibits the phosphorylation of VEGFR-2 and induces in vivo tumor growth arrest. Everolimus, a rapamycin derivative, inhibits mTOR, which is involved in cell survival and located downstream toVEGFR-2. It stops production of angiogenic growth factors in several neuroendocrine tumors.To date few genetic alterations were identified in ACT involving adrenocortical tumorigenesis signaling pathways; in particular the Ras/Raf/MEK/ERK and the Wnt/β-catenin signaling pathways seem to be often altered. β-catenin constitutive activation is an alteration frequently found in ACT. It is a multifunctional molecule involved in the processes of cell adhesion together with cadherin (E-cadherin and N-cadherin). Cadherins have been implicated in the development of many cancers, but information regarding their expression in the ACT is very limited.Aim. The objective of this study is: a) to evaluate the expression of VEGF, VEGFR-1 and VEGFR-2 in normal and tumoral adrenocortical tissues; b) to examine the effect of the two drugs, sorafenib and everolimus, in vitro on cellular viability, on apoptosis and on signal pathways of 2 stabilized lines (H295R, SW13) and in ACT primary cultures and in vivo in xenografts mouse models; c) to analyze the presence of genetic alterations in key components of the Ras/Raf/MEK/ERK signaling pathway (BRAF, H-RAS, K-RAS, N-RAS genes) and of Wnt/β-catenin signaling pathway (CTNNB1 and AXIN2 genes) and to investigate the β-catenin expression in relation to the cell adhesion molecules E-cadherin and N-cadherin.Material and Methods. 24 adrenocortical carcinomas (ACC), 37 aldosterone producing adenoma (APA), 28 cortisol producing adenoma (CPA), 6 non-secreting adenomas (NSA) and 8 normal adrenal gland tissues (NA) were collected. The VEGF and its receptors (VEGFR-1 and VEGFR-2) gene expression was evaluated in 63 ACT by real-time PCR. In cell lines (SW13 and H295R) and in primary ACT cultures, cell viability was observed by incubating sorafenib and everolimus in a range of concentrations from 10 µM to 0.1 nM by MTT test. By fluorescence microscopy (TUNEL) and flow cytometric analysis (Annexin-V), apoptosis was evaluated; by western blot, the involvement of PI(3)K/Akt/mTOR and in Ras/Raf/MEK/ERK signaling pathways was analyzed. The effects of drugs, alone or in combination, were tested in vivo in ACC xenografted models.By high resolution melting analysis (HRM), mutation analysis was performed on 95 ACT on BRAF (exons 11 and 15), H-RAS (exons 2 and 3), N-RAS (exons 2 and 3), K-RAS (exons 2 and 3), CTNNB1 (exon 3), AXIN2 (exon 7). Only samples with altered melting curves were sequenced. Finally, by real-time PCR and immunohistochemistry (IHC), β-catenin, N-cadherin and E-cadherin gene expression was evaluated in 68 ACT.Results. VEGF, VEGFR-1, VEGFR-2 expression was found in both adrenocortical normal and tumoral tissues. Compared to normal adrenal glands, a significant VEGF over-expression was observed in 65% (12/18) (P = 0.049) ACC and in 61% (20/33) (P = 0.025) APA. In SW13 and H295R cell viability, sorafenib and everolimus showed a dose-dependent response, while by fluorescence (TUNEL) and by flow cytometry (Annexin V) the compounds revealed an apoptotic effect. By western blot, sorafenib induced a complete decrease in Akt, ERK1/2 and p70S6K phosphorylation, while everolimus totally abolished p70S6K phosphorylation. Out of 8 primary cultures, 3 ACC and 3 ACA significantly responded to sorafenib and everolimus treatments. In vivo experiment a significant reduction of the tumor mass and an increase in median survival (especially in xenograft subjected to combined treatment) were observed.In HRM analisys some alterations in key components of the Ras/Raf/MEK/ERK signaling pathway were found, i.e. 2 BRAF mutations and 4 H-RAS mutations. In Wnt/β-catenin signaling pathway 18 alterations in CTNNB1 gene (5 APA, 6 CPA, 2 NSA, 5 ACC) and a single mutation in AXIN2 gene in H295R cells were observed. In RT-PCR β-catenin is over-expressed in approximately 50% of ACC (12/24) and in 51% of ACA (24/47). By IHC a significant accumulation of cytoplasmic and/or nuclear β-catenin has been observed in 47% of ACC (7/15) and 33% of ACA (11/33). In all ACT expression of E-cadherin was not detected. By RT-PCR N-cadherin down-regulation has been found in 75% of ACC (18/24) and in 60% of ACA (28/47). Similar results were obtained by IHC: N-cadherin down-regulation was observed in 100% (15/15) ACC and in 55% (18/33) ACA.Conclusion. Our data underline the importance of angiogenesis in adrenocortical tumors system. Anti-VEGF strategies, such as new tyrosine kinases and mTOR inhibitors currently used in different tumors, may represent a new therapeutic tool for adrenocortical tumors. The identification of new anti-angiogenic and Wnt/β-catenin signaling targets has contributed to a better understanding of adrenocortical tumorigenesis and to generate the basis for the development of new targeted drugs (targeted therapy)." @default.
• W89726717 created "2016-06-24" @default.
• W89726717 creator A5067429321 @default.
• W89726717 date "2013-01-30" @default.
• W89726717 modified "2023-09-27" @default.
• W89726717 title "Aspetti di genetica molecolare e possibili implicazioni terapeutiche nei tumori corticosurrenalici" @default.
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