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Rubin, Beatrice (2013) Aspetti di genetica molecolare e possibili implicazioni terapeutiche nei tumori corticosurrenalici. [Tesi di dottorato]

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Abstract (inglese)

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).

Abstract (italiano)

Presupposti dello studio. I più comuni tumori corticali della ghiandola surrenalica (ACT) sono tumori benigni definiti adenomi corticosurrenalici (ACA) con una incidenza stimata di circa 7,3%. I tumori maligni, i carcinomi corticosurrenalici (ACC), sono invece rare neoplasie endocrine, con prognosi infausta ed incidenza di circa 1-2 casi per milione. I trattamenti per l’ACC sono inefficaci nella maggior parte dei casi ed attualmente si basano sull’uso di mitotane (o,p’DDD) con o senza i tradizionali agenti chemioterapici. Poiché le prognosi di ACA o di ACC sono estremamente differenti è importante differenziare queste due tipologie di tumore.
Numerosi tumori attraverso il processo di angiogenesi stimolano la crescita dei vasi ematici dell’ospite. Recentemente è stata osservata una over-espressione del fattore di crescita endoteliale vascolare (VEGF) negli ACC ed i recettori di VEGF (VEGFR-1 e VEGFR-2) trovati anch’essi sulle cellule tumorali, suggeriscono un possibile effetto autocrino di VEGF per la crescita cellulare.
Il farmaco sorafenib, un inibitore multichinasico, inibisce la fosforilazione di VEGFR-2 ed induce in vivo l’arresto della crescita di alcuni tumori. Il farmaco everolimus, analogo della rapamicina, inibisce mTOR coinvolto nella sopravvivenza cellulare e situato valle di VEGFR-2; è inoltre in grado bloccare la produzione di fattori pro-angiogenici in molti tumori neuroendocrini.
Ad oggi, le alterazioni genetiche note che colpiscono gli ACT sono limitate ed inoltre nella tumorigenesi corticosurrenalica sono coinvolte una grande varietà di vie del segnale, in particolar modo la via del segnale di Ras/Raf/MEK/ERK e la via di Wnt/β-catenina risultano spesso alterate. Un’alterazione frequentemente riscontrata negli ACT è l’attivazione costitutiva della β-catenina, una molecola multifunzionale coinvolta anche nei processi di adesione cellulare assieme alle caderine (E-caderina ed N-caderina). Le caderine sembrano essere coinvolte nello sviluppo di molti carcinomi, ma le informazioni riguardanti la loro espressione negli ACT è molto limitata.

Scopo. L’obbiettivo dello studio è stato quello di: a) valutare l’espressione di VEGF, VEGFR-1 e VEGFR-2 nei tessuti surrenalici normali e/o tumorali; b) esaminare l’effetto dei due farmaci, sorafenib ed everolimus, in vitro sulla vitalità cellulare, sull’apoptosi e su alcune pathways cellulari in linee stabilizzate (H295R, SW13), in colture primarie di ACT ed in vivo in modelli murini xenotrapiantati; c) analizzare la presenza di alterazioni geniche nei componenti chiave della via del segnale di Ras/Raf/MEK/ERK (studiando i geni BRAF, H-RAS, K-RAS, N-RAS) e nella via del segnale di Wnt/β-catenina (valutando i geni CTNNB1 e AXIN-2) ed indagare l’espressione della β-catenina in relazione alle molecole di adesione cellulare E-caderina ed N-caderina.

Materiali e Metodi. Sono stati raccolti 24 carcinomi corticosurrenalici (adrenocortical carcinoma, ACC), 37 adenomi secernenti aldosterone (aldosterone producing adenoma, APA), 28 adenomi secernenti cortisolo (cortisol producing adenoma, CPA), 6 adenomi non secernenti (non-secreting adenoma, NSA) e 8 campioni di surrene normale (normal adrenal, NA). L’espressione genica di VEGF e dei suoi recettori (VEGFR-1 e VEGFR-2) è stata valutata in 63 ACT tramite real-time PCR. Nelle linee cellulari (SW13 e H295R) e nelle colture primarie corticosurrenaliche, attraverso il test MTT è stata osservata la vitalità cellulare incubando con sorafenib ed everolimus in un range di concentrazioni da 10 μM a 0,1 nM. In microscopia a fluorescenza (TUNEL) e dall’analisi citofluorimetrica (Anessina V) è stato valutato il grado di apoptosi indotto dai farmaci e tramite western blotting è stato analizzato il loro possibile coinvolgimento nelle vie di PI(3)K/Akt/mTOR e di Ras/Raf/MEK/ERK. Gli effetti dei farmaci, da soli o in combinazione, sono stati testati poi in vivo in modelli murini di ACC xenotrapiantati con cellule H295R ed SW13. Attraverso l’analisi di high resolution melting (HRM) abbiamo ricercato in 95 ACT la presenza di mutazioni attivanti nei geni BRAF (esoni 11 e 15), H-RAS (esoni 2 e 3), N-RAS (esoni 2 e 3), K-RAS (esoni 2 e 3), CTNNB1 (esone 3), AXIN2 (esone 7). I campioni aventi curve di melting dubbie o alterate sono stati sottoposti tutti al sequenziamento. Infine, è stata valutata in 68 ACT l’espressione genica di β-catenina, N-caderina ed E-caderina attraverso le tecniche di real-time PCR e di immunoistochimica (IHC).

Risultati. Sia i tessuti corticosurrenalici normali che tumorali esprimono VEGF, VEGFR-1, VEGFR-2. Rispetto ai surreni normali, una significativa over-espressione di VEGF è stata osservata in circa il 65% (12/18) (P = 0.049) degli ACC analizzati ed in circa il 61% (20/33) (P = 0.025) degli APA. Nella valutazione della vitalità cellulare le cellule SW13 ed H295R rispondono in modo dose-dipendente ai farmaci sorafenib ed everolimus mentre in fluorescenza ed in citofluorimetria è stato osservato un effetto apoptotico. Mediante western, sorafenib induce una completa diminuzione della fosforilazione di Akt, ERK1/2 e P70S6K mentre everolimus, abolisce totalmente la fosforilazione di p-P70S6K. Delle 8 colture primarie sottoposte ai farmaci, 3 carcinomi e 3 adenomi rispondono in modo significativo sia al trattamento con sorafenib che all’everolimus, mentre 2 casi di ACC sono resistenti ad entrambi i farmaci. In vivo è stata osservata una significativa riduzione della massa tumorale ed un aumento della sopravvivenza mediana soprattutto nei topi sottoposti al trattamento farmacologico combinato.
Attraverso le indagini in HRM sono state riscontate alcune alterazioni nei componenti della via del segnale di Ras/Raf/MEK/ERK: 2 ACC con mutazioni nel gene BRAF e 1 APA, 1 CPA e 2 ACC con mutazioni nel gene H-RAS. Per quanto riguarda l’indagine genetica della via del segnale di Wnt/β-catenina sono state osservate 18 alterazioni nel gene CTNNB1 (5 APA, 6 CPA, 2 NSA, 5 ACC) ed una sola mutazione nel gene AXIN2 nelle cellule H295R. In RT-PCR l’espressione di β-catenina è over-espressa in circa 50% degli ACC (12/24) ed in circa il 51% degli ACA (24/47) mentre in IHC circa il 47% degli ACC (7/15) ed il 33% degli ACA (11/33) presenta un notevole accumulo citoplasmatico e/o nucleare di β-catenina. In tutti gli ACT non è stata rilevata l’espressione di E-caderina, mentre per quanto riguarda N-caderina, in RT-PCR circa il 75% degli ACC (18/24) ed il 60% degli ACA (28/47) possiedono una down-regolazione. Risultati simili sono stati ottenuti in IHC in cui il 100% degli ACC (15/15) e il 55% degli ACA (18/33) presentano una down-regolazione di N-caderina.

Conclusioni. I nostri dati sottolineano l’importanza del sistema angiogenico nei tumori corticosurrenalici. I nuovi inibitori tirosin-chinasici e di mTOR attualmente usati in alcuni tumori come strategie anti-VEGF potrebbero rappresentare un nuovo strumento terapeutico per i tumori della ghiandola surrenale. L’identificazione quindi di nuovi target molecolari anti-angiogenetici e di target nella via del segnale di Wnt/β-catenina ha contribuito ad una migliore comprensione ed a un approfondimento della tumorigenesi corticosurrenalica generando le basi per lo sviluppo di nuovi farmaci mirati (target therapy).

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Tipo di EPrint:Tesi di dottorato
Relatore:Scaroni, Carla
Correlatore:Mantero, Franco
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > METODOLOGIA CLINICA, SCIENZE ENDOCRINOLOGICHE E DIABETOLOGICHE
Data di deposito della tesi:30 Gennaio 2013
Anno di Pubblicazione:30 Gennaio 2013
Parole chiave (italiano / inglese):Tumori corticosurrenalici, Angiogenesi tumorale, Sorafenib, Everolimus, Via del segnale di Wnt/Beta-catenina. / Adrenocortical tumors, Tumor angiogenesis, Sorafenib, Everolimus, Wnt/Beta-catenin signaling pathway.
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/13 Endocrinologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:5744
Depositato il:10 Ott 2013 14:38
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