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Finco, Isabella (2010) Valutazione di nuovi target terapeutici in tumore del surrene e ruolo di sonic hedgehog nella biologia della ghiandola surrenalica. [Tesi di dottorato]

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Abstract (inglese)

Introduction: Benign adrenal tumors are relatively common with occurrences of 3-7% of the population. Malignant adrenal tumors or adrenocortical carcinomas (ACC) are relatively rare but highly malignant and presents with extremely poor prognosis. Somatostatin (SST) is a widely distributed polypeptide that modulates endocrine and exocrine secretion, cell proliferation and apoptosis via five somatostatin receptors (SSTR1-5). Somatostatin’s inhibitory effects on tumor growth may be the result of it suppressing the synthesis and/or secretion of growth factors and growth-promoting hormones. Octreotide and SOM230 are multi-ligand SST analogues with high affinity for SSTRs. In human adrenal gland the expression of SSTRs was previously demonstrated by immunohistochemistry, but only very few information are available about the effectiveness of somatostatin analogs in ACC. Previous evidence showed that a SSTR1 selective agonist inhibits vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) expression. Moreover, a new steroidogenic tissue specific angiogenic factor (EG-VEGF) has been described and its role in adrenal tumors is currently unknown. The ability of certain tumors to escape anti-angiogenic strategies might be due, at least in part, to the expression of organ specific angiogenic molecules, like EG-VEGF. Aim of the study: In the literature, very little information is available on the effect of somatostatin analogs on adrenal tumors, aim of this study is to analyze the expression of SSTRs and angiogenic factors in adrenocortical tumors, and to observe the effect of a somatostatin analog (SOM230) on hormone secretion, cell viability and angiogenesis in adrenal cells. Material, Subjects and Methods: SSTR and angiogenic factor expression was analyzed by quantitative real-time PCR (qPCR) in 13 adrenocortical carcinomas (ACC), 24 aldosteroneproducing adenomas (APA), 11 cortisol-producing adenomas (CPA) and 7 normal adrenals (NA), and verified by immunohistochemistry for 4 SSTRs in 14 samples. The effect of SOM230 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by RIA whereas the effect on cell viability in H295R by MTT test. VEGF and EG-VEGF mRNA levels after SOM230 treatment in H295R were detected by qPCR. Results: SSTR1 and SSTR2 mRNA was expressed in 100% of adrenal tumors. ACC exhibited an increase in almost all SSTRs whereas only some APA over-expressed SSTR3 and SSTR1 compared to NA. CPA expressed SSTR similar to NA. IHC confirmed the mRNA expression data. Furthermore SOM230 at nanomolar concentrations inhibited hormone secretion in primary adrenal cultures and H295R cells but, as we found for the treatment with octreotide, no effect on cell viability was evident. VEGF, VEGFR1, VEGFR2 and EG-VEGF mRNA was highly expressed in all our tissues; PROKR1 mRNA levels were low, moreover we found its presence in 72,7% ACC and CPA and in 90% APA. 64% of ACC had VEGF and EG-VEGF overxpressed, whether APA had a marked overexpression of VEGF and VEGFR1. The CPA’s expression pattern was similar to NA. SOM230 also inhibits VEGF and EG-VEGf mRNA expression at concentrations of 10-6M and 10-8M in H295R cells. Conclusions: The findings of SSTR over-expression (particularly in ACC) and the hormone secretion inhibition by SOM230 suggest a potential therapeutic role for this broad-spectrum somatostatin analog in adrenal tumors. This idea is also supported by the angiogenic factor overexpression found in ACC and APA and by the inhibitory effects on two of them exhibited by SOM230. Background (I): Development of the mammalian adrenal gland is regulated by a diverse network of growth and transcription factors. The adrenal cortex is a critical steroidogenic endocrine tissue, generated at least in part from the coelomic epithelium of the urogenital ridge. Neither the intercellular signals that regulate cortical development and maintenance nor the lineage relationships within the adrenal are well defined. Sonic Hedgehog (Shh) is a lingand of the Hedgehog family (Hh) and its major functions are found in the body patterning, fate specification, cell proliferation and cell survival. Gli1, Gli2, and Gli3 are transcription factors transcriptionally regulated by Smoothend (Smo), an Hh receptor inhibited by Patched in absence of Hh. Moreover, several studies have observed the connection between Shh pathway and Wnt pathway, a very important pathway in the developing adrenal and in the formation of adrenal tumors. Material and Methods (I): qPCR and RT-PCR analysis for the Hh pathaway genes were carried out on RNA from murine wild type (wt) adrenals and from Y1 cells; RT-PCRs for Wnt ligands were performed on RNA from transgenic animals and their controls. Adrenals from reporter mice for Shh, Ptch and Gli1 expression were X-gal stained to detect the expression of these genes in the tissues.
The following crossings were also made to localize the Gli1 gene expression in the adrenal tissue. Gli1CreERT2 mice were breed with R26R reporter mice. For the embryological study, pregnant females were IP injected with tamoxifen (100mg/kg) at 13,5dpc. The animals were sacrified at the following time points: 16,5dpc, 18,5dpc and P1. For studies on adults, Gli1CreERT2-R26R mice, carrying both transgenes in heterozygosis, were injected at P21 with 100mg/kg/die tamoxifen for 14 days, then the tissues were harvested at 9, 25 and 57 weeks of age and stained for X-gal.
To overexpress Smo in Gli1-positive cells, Gli1CreERT2 mice were crossed with SmoM2EYFP mice. Pregnant females were injected with tamoxifen and sacrified at 16,5dpc or 18,5dpc or tissues were harvested from pups 1day after their birth. Gli1CreERT2-SmoM2EYFP heterozygous mice were injected at P21 with tamoxifen for 14 days. The tissues were harvested at 5, 10 or 28 weeks after birth. The tissues were stained by immunofluorescence. Results (I):We found the presence of all the Hh pathway genes in wt adrenal, with the exception of Ptch2; Shh is the most expressed ligand of the Hh family in wt adrenal. We found Shh being expressed in the subcapsular region, whereas Ptch1 and Gli1 in the adrenal capsule. Gli1 is expressed both in embryos and in adult mice in the adrenal capsule; we also found Gli1-positive clusters in the cortex. The Smo verexpression in adults results in a thinner capsular COUPTII positive-cells layer, in an increase of proliferation and in a wider (at 28 week-time point) or stronger (at 10 weeks)
β-catenin expression. The results were confirmed by qPCR performed on RNA extracted from controlateral adrenals. To investigate which Wnt ligand could be involved in this process, we determinated by RT-PCR for all Wnt ligands that there was a change in the Wnt2a, Wnt4, Wnt5a and -5b, Wnt11 and Wnt15 expression. In embryos we observed an increase of the adrenal size and more proliferating cells. Conclusions (I): In this study we found the expression of Hh pathways genes in the adrenal, moreover we observed Shh expression in the subcapsula adrenal zone, whereas Ptch and Gli1 expressing cells are identified in the capsule. We also noticed that Gli1-positive cells, organized in clusters, migrate centripetally and become part of the adrenocortex, supporting the idea of the adrenal capsule providing cell progenitors. Overexpressing Smo in Gli1 expressing cells increased the proliferation and resulted in a thinner capsule, so in the next future we will study which cell population decreased in the capsule. We also noticed an increase of β-catenin expression and/or of β-catenin expressiong cells at different time points, thus we analyzed which Wnt ligand is expressed in a different way compared to our controls by RT-PCR, and now we will deepen our analysis by qPCR. All the obtained results are promising because we identified an important role of the Gli1 expressing cells and, at the same time, a potential relationship between Wnt and Shh pathway in the adrenal development and maintenance.

Abstract (italiano)

Introduzione: I tumori surrenalici benigni sono relativamente comuni con un’incidenza del 3-7%. Invece i tumori maligni, o carcinomi della corticale del surrene (ACC), sono piuttosto rari ma altamente maligni e presentano una prognosi infausta. La somatostatina (SST) è un polipeptide ampiamente distribuito che modula la secrezione endocrina ed esocrina, la proliferazione cellulare e l'apoptosi tramite cinque recettori somatostatinici (SSTR1-5). Gli effetti inibitori della somatostatina sulla crescita tumorale possono essere il risultato della soppressione della sintesi e/o del rilascio di fattori di crescita e ormoni promuoventi la crescita. Octreotide e SOM230 sono analoghi multi-ligando di SST con alta affinità per i recettori SST L’espressione dei recettori SST è stata dimostrata in ghiandole surrenali umane mediante immunoistochimica, ma poche sono le informazioni disponibili riguardanti l’efficacia di analoghi della somatostatina in ACC. Studi precedenti hanno mostrato che un agonista selettivo di SSTR1 inibisce il fattore di crescita vascolare endoteliale (VEGF) e l’espressione del suo recettore (VEGFR2). È stato inoltre descritto un nuovo fattore angiogenico specifico dei tessuti steroidei (EG-VEGF), e il suo ruolo nei tumori surrenalici è attualmente ignoto. La capacità di alcuni tumori di sfuggire
alle terapie anti-angiogeniche potrebbe essere dovuta, almeno in parte, all'espressione di molecole angiogeniche organo-specifiche, come EG-VEGF. Scopo dello studio: In letteratura, pochissime informazioni sono disponibili sull'effetto di analoghi della somatostatina in tumori surrenalici; pertanto scopo di questo studio è quello di analizzare l'espressione di SSTRs e di fattori angiogenici nei tumori cortico-surrenalici, nonché di osservare l'effetto di un analogo della somatostatina (il SOM230) sulla secrezione ormonale, sulla vitalità cellulare e sull’angiogenesi in cellule surrenaliche. Materiali e Metodi: Tramite real-time PCR quantitativa (qPCR) è stata analizzata l’espressione dei recettori SST e dei fattori angiogenici in 13 carcinomi della corticale del surrene (ACC), in 24 adenomi secernenti aldosterone (APA), in 11 adenomi secernenti cortisolo (CPA) e in 7 ghiandole surrenali normali (NA); successivamente si è verificata l’espressione di 4 SSTR mediante analisi immunoistochimica in 14 campioni. L'effetto di SOM230 sulla secrezione di cortisolo o di aldosterone in colture di cellule H295R e in colture primarie è stato determinato mediante RIA, e l'effetto sulla vitalità di cellule H295R con MTT test.I livelli di espressione di VEGF e EG-VEGF dopo trattamento di cellule H295R con SOM230 sono stati studiati mediante qPCR.
Risultati: L’mRNA per SSTR1 e SSTR2 è stato espresso nel 100% dei tumori surrenalici. ACC ha dato un aumento in quasi tutti i SSTR, laddove solo alcuni APA, comparati con NA, overesprimevano SSTR3 e SSTR1. CPA esprimevano SSTR similmente a NA. L’immunoistochimica ha confermato i dati relativi all'espressione di mRNA. Inoltre SOM230 a concentrazioni nanomolari ha inibito la secrezione ormonale in colture primarie e in cellule H295R ma, come per il trattamento con octreotide, non ha sortito alcun effetto sulla vitalità cellulare.
L’mRNA di VEGF, VEGFR1, VEGFR2 e EG-VEGF era altamente espresso in tutti i nostri tessuti; i livelli di PROKR1erano invece bassi, inoltre abbiamo trovato la presenza di questo gene nel 72,2% di ACC e CPA e nel 90%di APA. Il 64% degli ACC aveva VEGF e EG-VEGF overespressi, mentre gli APA avevano una marcata overespressione di VEGF e VEGFR1. Il pattern d’espressione dei CPA era simile a quello dei NA. SOM230 inibisce anche l’espressione dell’mRNA di VEGF e EG-VEGF alle concentrazioni di 10-6M and 10-8M in cellule H295R.
Conclusioni: Le evidenze della sovraespressione di SSTR (in particolare in ACC) e l’inibizione della secrezione ormonale da parte di SOM230 suggerisce un potenziale ruolo terapeutico per questo analogo ad ampio spettro della somatostatina nei tumori surrenalici. Questa idea è supportata anche dall’overespressione dei fattori angiogenici trovata in ACC e APA e dagli effetti inibitori esercitati da SOM230 su due di essi. Introduzione (I): Lo sviluppo del surrene nel mammifero è regolato da una complessa rete di fattori di crescita e di trascrizione. La corteccia surrenalica è un tessuto endocrinologico steroidogenico critico, generata almeno in parte dall’epitelio celomico della cresta urogenitale. Né i segnali intracellulari che regolano lo sviluppo e il mantenimento della corteccia, né le relazioni tra i diversi lineage nel surrene sono ben definiti Sonic Hedgehog (Shh) è un ligando della famiglia Hedgehog (Hh) e le sue maggiori funzioni sono state trovate nel patterning degli assi corporei, nella specificazione del fato di una cellula, nella proliferazione e nella sopravvivenza cellulare. Gli1, Gli2 e Gli3 sono fattori di trascrizione regolati trascrizionalmente da Smoothened (Smo), un recettore inibito da Patched in assenza di Hh. Inoltre, diversi studi hanno osservato la connessione tra la via di segnalazione di Shh e quella di Wnt, un pathway molto importante nello sviluppo surrenalico e nella formazione di tumori del surrene.
Scopo dello studio (I): Oggi molto poco è conosciuto sul ruolo di Shh nella biologia del surrene. Scopo di questo studio è caratterizzare l’espressione dei componenti della via di
segnalazione di Hh, in particolare di Gli1 con analisi molecolari e istologiche, nella ghiandola surrenalica di modelli murini, e di studiare molecolarmente e istologicamente, mediante
immunofluorescenza, i fenotipi di un modello murino caratterizzato da un’espressione costitutivamente attiva di Smo.
Materiali e metodi (I): Analisi di qPCR e RT-PCR sono state condotte su RNA estratto da surreni di topi wild type (wt) e da cellule Y1; reazioni di RT-PCR per i ligandi Wnt sono state
eseguite su RNA proveniente da animali transgenici e dai loro controlli. Surreni di topi reporter per l’espressione di Shh, Ptch e Gli1 sono stati sottoposti a X-gal staining per individuare la loro espressione nei tessuti. Per localizzare l’espressione del gene Gli1 nel tessuto surrenalico sono stati fatti i seguenti incroci. Topi Gli1CreERT2 sono stati incrociati con topi reporter R26R. Per lo studio embriologico, femmine di topo gravide sono state iniettate intraperitonealmente (IP) con tamoxifen (100mg/kg) nel giorno 13,5dpc. Gli animali sono stati sacrificati ai seguenti time
point: 16,5dpc, 18,5dpc e P1. Per studi sugli adulti, topi Gli1CreERT2-R26R portanti in eterozigosi entrambi i transgeni, sono stati iniettati con tamoxifen 100mg/kg/die dal
ventunesimo giorno di vita (P21) per 14 giorni, sono stati poi raccolti i tessuti a 9, 25 e 57 settimane d’età e sottoposti a X-gal staining. Per sovraesprimere Smo nelle cellule positive a Gli1, topo Gli1CreERT2 sono stati incrociati con topi SmoM2EYFP. Femmine gravide sono state iniettate IP con tamoxifen e sacrificate a 16,5 o 18,5 dpc, oppure i tessuti sono stati raccolti da cuccioli di topo di un giorno di vita. Topi eterozigoti Gli1CreERT2-SmoM2EYFP sono stati iniettati dal P21 con tamoxifen per 14 giorni. I tessuti sono stati raccolti a 5, 10 o 28 settimane di vita. I tessuti sono stati sottoposti a
immunofluorescenza. Risultati (I): Abbiamo trovato la presenza di tutti i geni coinvolti nella via di segnalazione di Hh nel surrene wt, con l’eccezione di Ptch2; Shh è il ligando della famiglia Hh più espresso nel surrene wt. Abbiamo trovato la sua espressione nella regione sotto-capsulare del surrene, mentre Ptch1 e Gli1 erano nella capsula surrenalica. Gli1 è espresso nella capsula sia negli embrioni che nei topi adulti, inoltre abbiamo osservato gruppi di cellule positivi per Gli1 nella corteccia surrenalica.
La sovraespressione di Smo negli adulti porta ad uno strato di cellule capsulari positive per COUPTFII più sottile, ad un incremento della proliferazione ed a un’espressione di β-catenina più diffusa (a 28 settimane) o più forte (a 10 settimane). I risultati sono stati confermati mediante qPCR svolta su RNA estratto dai surreni controlaterali. Per investigare quale ligando Wnt possa essere coinvolto in questo processo, abbiamo determinato mediante RTPCR che, rispetto ai nostri controlli, vi era un cambiamento nell’espressione di Wnt2a, Wnt4, Wnt5a e 5b, Wnt11 e Wnt 15. Negli embrioni abbiamo osservato un aumento delle dimensioni del surrene e delle cellule proliferanti. Conclusioni (I): In questo studio abbiamo trovato l’espressione dei geni coinvolti nella via di segnalazione di Hh nel surrene, inoltre abbiamo osservato che l’espressione di Shh è localizzata nella zona subcapsulare del surrene, mentre quella di Ptch e Gli1 è confinata nella capsula surrenalica. Abbiamo però osservato che cellule Gli1-positive, organizzate in piccoli gruppi, migrano in maniera centripeta e diventano parte della corteccia surrenalica, supportando l’idea che la capsula surrenalica sia la sede di progenitori cellulari.
L’overespressione di Smo nelle cellule esprimenti Gli1 ha aumentato la proliferazione e al contempo è risultata in una capsula più sottile, perciò nel prossimo futuro studieremo quale
popolazione cellulare è diminuita nella capsula. Abbiamo inoltre notato un aumento dell’espressione di β-catenina e/o delle cellule esprimenti β-catenina nei diversi time point, abbiamo quindi analizzato quale ligando Wnt è espresso in maniera diversa rispetto ai nostri controlli mediante RT-PCR, e adesso approfondiremo l’analisi mediante qPCR. Tutti i risultati ottenuti sono promettenti perché abbiamo individuato un ruolo importante delle cellule esprimenti Gli1 e, allo stesso tempo, una potenziale relazione tra le vie di Wnt e Shh nello sviluppo e nel mantenimento del surrene

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Tipo di EPrint:Tesi di dottorato
Relatore:Mantero, Franco
Dottorato (corsi e scuole):Ciclo 22 > Scuole per il 22simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > METODOLOGIA CLINICA E SCIENZE ENDOCRINOLOGICHE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:14 Settembre 2010
Parole chiave (italiano / inglese):Surrene, Somatostatina, Angiogenesi, Sonic hedgehog
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/13 Endocrinologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Medicina Clinica e Sperimentale
Codice ID:3188
Depositato il:14 Mar 2011 09:10
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