Go to the content. | Move to the navigation | Go to the site search | Go to the menu | Contacts | Accessibility

| Create Account

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

Full text disponibile come:

PDF Document - Submitted Version

Abstract (english)

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 (italian)

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

Statistiche Download - Aggiungi a RefWorks
EPrint type:Ph.D. thesis
Tutor:Mantero, Franco
Data di deposito della tesi:UNSPECIFIED
Anno di Pubblicazione:14 September 2010
Key Words: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
Simple Metadata
Full Metadata
EndNote Format


I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. D. Andreani, G.M., D. Andreani, Trattato di diagnostica funzionale endocrinologica. 1984: PICCIN. Cerca con Google

2. Else, T. and G.D. Hammer, Genetic analysis of adrenal absence: agenesis and aplasia. Trends Endocrinol Metab, 2005. 16(10): p. 458-68. Cerca con Google

3. Wrobel, K.H. and F. Suss, On the origin and prenatal development of the bovine adrenal gland. Anat Embryol (Berl), 1999. 199(4): p. 301-18. Cerca con Google

4. Sidhu, S., et al., Clinical and molecular aspects of adrenocortical tumourigenesis. ANZ J Surg, 2003. 73(9): p. 727-38. Cerca con Google

5. de Fraipont, F., et al., Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab, 2005. 90(3): p. 1819-29. Cerca con Google

6. Krulich, L., A.P. Dhariwal, and S.M. McCann, Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology, 1968. 83(4): p. 783-90. Cerca con Google

7. Hellman, B. and A. Lernmark, Evidence for an inhibitor of insulin release in the pancreatic islets. Diabetologia, 1969. 5(1): p. 22-4. Cerca con Google

8. Burgus, R., et al., Primary structure of somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone. Proc Natl Acad Sci U S A, 1973. 70(3): p. Cerca con Google

684-8. Cerca con Google

9. Siler, T.M., et al., Inhibition of growth hormone release in humans by somatostatin. J Clin Endocrinol Metab, 1973. 37(4): p. 632-4. Cerca con Google

10. Patel, Y.C., Somatostatin and its receptor family. Front Neuroendocrinol, 1999. 20(3):p. 157-98. Cerca con Google

11. Grimberg, A., Somatostatin and cancer: applying endocrinology to oncology. Cancer Biol Ther, 2004. 3(8): p. 731-3. Cerca con Google

12. Goodman, R.H., et al., Nucleotide sequence of a cloned structural gene coding for a precursor of pancreatic somatostatin. Proc Natl Acad Sci U S A, 1980. 77(10): p. 5869-73. Cerca con Google

13. Goodman, R.H., et al., Pre-prosomatostatins. Products of cell-free translations of messenger RNAs from anglerfish islets. J Biol Chem, 1980. 255(14): p. 6549-52. Cerca con Google

14. Patel, Y.C. and W. O'Neil, Peptides derived from cleavage of prosomatostatin at carboxyl- and amino-terminal segments. Characterization of tissue and secreted forms in the Cerca con Google

rat. J Biol Chem, 1988. 263(2): p. 745-51. Cerca con Google

15. Kumar, U. and M. Grant, Somatostatin and somatostatin receptors. Results Probl Cell Differ, 2010. 50: p. 137-84. Cerca con Google

16. Susini, C. and L. Buscail, Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol, 2006. 17(12): p. 1733-42. Cerca con Google

17. Bruno, J.F., et al., Molecular cloning and functional expression of a brain-specific somatostatin receptor. Proc Natl Acad Sci U S A, 1992. 89(23): p. 11151-5. Cerca con Google

18. Meyerhof, W., et al., Molecular cloning of a somatostatin-28 receptor and comparison of its expression pattern with that of a somatostatin-14 receptor in rat brain. Proc Natl Acad Cerca con Google

Sci U S A, 1992. 89(21): p. 10267-71. Cerca con Google

19. O'Carroll, A.M., et al., Molecular cloning and expression of a pituitary somatostatin receptor with preferential affinity for somatostatin-28. Mol Pharmacol, 1992. 42(6): p.939-46. Cerca con Google

20. Yamada, Y., et al., Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase. Mol Endocrinol, 1992. 6(12): p. 2136-42. Cerca con Google

21. Baumeister, H. and W. Meyerhof, Gene regulation of somatostatin receptors in rats. J Physiol Paris, 2000. 94(3-4): p. 167-77. Cerca con Google

22. Kreienkamp, H.J., et al., Functional annotation of two orphan G-protein-coupled receptors, Drostar1 and -2, from Drosophila melanogaster and their ligands by reverse pharmacology. J Biol Chem, 2002. 277(42): p. 39937-43. Cerca con Google

23. Weckbecker, G., et al., Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov, 2003. 2(12): p. 999-1017. Cerca con Google

24. Guillermet-Guibert, J., et al., Physiology of somatostatin receptors. J Endocrinol Invest, 2005. 28(11 Suppl International): p. 5-9. Cerca con Google

25. Ueberberg, B., et al., Differential expression of the human somatostatin receptor subtypes sst1 to sst5 in various adrenal tumors and normal adrenal gland. Horm Metab Res, 2005. 37(12): p. 722-8. Cerca con Google

26. Ricci, S., et al., Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide. Ann Oncol, 2000. 11(9): p. 1127-30. Cerca con Google

27. Bousquet, C., et al., Antiproliferative effect of somatostatin and analogs. Chemotherapy, 2001. 47 Suppl 2: p. 30-9. Cerca con Google

28. Vale, W., et al., Biologic and immunologic activities and applications of somatostatin analogs. Metabolism, 1978. 27(9 Suppl 1): p. 1391-401. Cerca con Google

29. Bauer, W., et al., SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci, 1982. 31(11): p. 1133-40. Cerca con Google

30. Patel, Y.C., Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest, 1997. 20(6): p. 348-67. Cerca con Google

31. Bruns, C., et al., SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory Cerca con Google

profile. Eur J Endocrinol, 2002. 146(5): p. 707-16. Cerca con Google

32. Ferrante, E., et al., Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr Relat Cancer, 2006. 13(3): p. 955-62. Cerca con Google

33. Hofland, L.J., et al., The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab, 2004. 89(4): p. 1577-85. Cerca con Google

34. Ma, P., et al., Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly. Clin Pharmacol Cerca con Google

Ther, 2005. 78(1): p. 69-80. Cerca con Google

35. Schmid, H.A., Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol, 2008. 286(1-2): p. 69-74. Cerca con Google

36. Bocci, G., et al., In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. Eur J Clin Invest, 2007. 37(9): p. 700-8. Cerca con Google

37. Folkman, J., et al., Isolation of a tumor factor responsible for angiogenesis. J Exp Med, 1971. 133(2): p. 275-88. Cerca con Google

38. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285 (21): p. 1182-6. Cerca con Google

39. Brem, H. and J. Folkman, Inhibition of tumor angiogenesis mediated by cartilage. J Exp Med, 1975. 141(2): p. 427-39. Cerca con Google

40. Senger, D.R., et al., Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 1983. 219(4587): p. 983-5. Cerca con Google

41. Shing, Y., et al., Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science, 1984. 223(4642): p. 1296-9. Cerca con Google

42. Ferrara, N. and W.J. Henzel, Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun, 1989. Cerca con Google

161(2): p. 851-8. Cerca con Google

43. Leung, D.W., et al., Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 1989. 246(4935): p. 1306-9. Cerca con Google

44. White, C.W., et al., Treatment of pulmonary hemangiomatosis with recombinant Cerca con Google

interferon alfa-2a. N Engl J Med, 1989. 320(18): p. 1197-200. Cerca con Google

45. Keck, P.J., et al., Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science, 1989. 246(4935): p. 1309-12. Cerca con Google

46. Klagsbrun, M. and S. Soker, VEGF/VPF: the angiogenesis factor found? Curr Biol 1993. 3(10): p. 699-702. Cerca con Google

47. O'Reilly, M.S., et al., Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol, 1994. 59: p. 471-82. Cerca con Google

48. Nyberg, P., L. Xie, and R. Kalluri, Endogenous inhibitors of angiogenesis. Cancer Res, 2005. 65(10): p. 3967-79. Cerca con Google

49. O'Reilly, M.S., et al., Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 1994. 79(2): p. 315-28. Cerca con Google

50. Relf, M., et al., Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived Cerca con Google

endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res, 1997. 57(5): p. 963-9. Cerca con Google

51. Ferrara, N., Vascular endothelial growth factor. Eur J Cancer, 1996. 32A(14): p. 2413-22. Cerca con Google

52. Chua, R.A. and J.L. Arbiser, The role of angiogenesis in the pathogenesis of psoriasis. Autoimmunity, 2009. 42(7): p. 574-9. Cerca con Google

53. Szekanecz, Z., et al., Angiogenesis and vasculogenesis in rheumatoid arthritis. Curr Opin Rheumatol, 2010. 22(3): p. 299-306. Cerca con Google

54. Arroyo, A.G. and M.L. Iruela-Arispe, Extracellular matrix, inflammation, and the angiogenic response. Cardiovasc Res, 2010. 86(2): p. 226-35. Cerca con Google

55. Glaser, S.S., E. Gaudio, and G. Alpini, Vascular factors, angiogenesis and biliary tract disease. Curr Opin Gastroenterol, 2010. 26(3): p. 246-50. Cerca con Google

56. Fernandez, M., et al., Angiogenesis in liver disease. J Hepatol, 2009. 50(3): p. 604-20. Cerca con Google

57. Folkman, J., Tumor angiogensis: role in regulation of tumor growth. Symp Soc Dev Biol, 1974. 30(0): p. 43-52. Cerca con Google

58. Folkman, J. and R. Cotran, Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol, 1976. 16: p. 207-48. Cerca con Google

59. Ferrara, N., Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol, 2002. 29(6 Suppl 16): p. 10-4. Cerca con Google

60. Gillies, R.J., et al., Causes and effects of heterogeneous perfusion in tumors. Neoplasia, 1999. 1(3): p. 197-207. Cerca con Google

61. Raghunand, N., R.A. Gatenby, and R.J. Gillies, Microenvironmental and cellular consequences of altered blood flow in tumours. Br J Radiol, 2003. 76 Spec No 1: p. S11-22. Cerca con Google

62. Dvorak, H.F., Angiogenesis: update 2005. J Thromb Haemost, 2005. 3(8): p. 1835-42. Cerca con Google

63. Hanahan, D. and R.A. Weinberg, The hallmarks of cancer. Cell, 2000. 100(1): p.57-70. Cerca con Google

64. Hanahan, D. and J. Folkman, Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996. 86(3): p. 353-64. Cerca con Google

65. Roskoski, R., Jr., Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol, 2007. 62(3): p. 179-213. Cerca con Google

66. Ferrara, N., Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev, 2004. 25(4): p. 581-611. Cerca con Google

67. Fantl, W.J., D.E. Johnson, and L.T. Williams, Signalling by receptor tyrosine kinases. Annu Rev Biochem, 1993. 62: p. 453-81. Cerca con Google

68. Berra, E., A. Ginouves, and J. Pouyssegur, The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep, 2006. 7(1): p. 41-5. Cerca con Google

69. Tischer, E., et al., The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem, 1991. 266(18): p. Cerca con Google

11947-54. Cerca con Google

70. Gaillard, I., et al., ACTH-regulated expression of vascular endothelial growth factor in the adult bovine adrenal cortex: a possible role in the maintenance of the microvasculature. J Cerca con Google

Cell Physiol, 2000. 185(2): p. 226-34. Cerca con Google

71. Thomas, M., et al., Role of adrenocorticotropic hormone in the development and maintenance of the adrenal cortical vasculature. Microsc Res Tech, 2003. 61(3): p. 247-51. Cerca con Google

72. Cherradi, N., et al., Antagonistic functions of tetradecanoyl phorbol acetate-induciblesequence 11b and HuR in the hormonal regulation of vascular endothelial growth factor messenger ribonucleic acid stability by adrenocorticotropin. Mol Endocrinol, 2006. 20(4): p. 916-30. Cerca con Google

73. Gospodarowicz, D., J.A. Abraham, and J. Schilling, Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Cerca con Google

Natl Acad Sci U S A, 1989. 86(19): p. 7311-5. Cerca con Google

74. Connolly, D.T., et al., Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest, 1989. 84(5): p. 1470-8. Cerca con Google

75. Hoeben, A., et al., Vascular endothelial growth factor and angiogenesis. Pharmacol Rev, 2004. 56(4): p. 549-80. Cerca con Google

76. Ng, Y.S., et al., Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn, 2001. 220(2): p. 112-21. Cerca con Google

77. Berse, B., et al., Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell, Cerca con Google

1992. 3(2): p. 211-20. Cerca con Google

78. de Fraipont, F., et al., Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. J Clin Endocrinol Metab, 2000. 85(12): p. 4734-41. Cerca con Google

79. Bernini, G.P., et al., Angiogenesis in human normal and pathologic adrenal cortex. J Clin Endocrinol Metab, 2002. 87(11): p. 4961-5. Cerca con Google

80. Robinson, C.J. and S.E. Stringer, The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci, 2001. 114(Pt 5): p. 853-65. Cerca con Google

81. Muller, Y.A., et al., Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci U S A, 1997. 94(14): p. 7192-7. Cerca con Google

82. Iyer, S., et al., Crystal structure of human vascular endothelial growth factor-B: identification of amino acids important for receptor binding. J Mol Biol, 2006. 359(1): p. Cerca con Google

76-85. Cerca con Google

83. Salven, P., et al., Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol, 1998. 153(1): p. 103-8. Cerca con Google

84. Joukov, V., et al., A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J, 1996. 15(2): p. 290-98. Cerca con Google

85. Joukov, V., et al., Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J, 1997. 16(13): p. 3898-911. Cerca con Google

86. Siegfried, G., et al., The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest, 2003. 111(11): p. 1723-32. Cerca con Google

87. Zhou, A., et al., Proteolytic processing in the secretory pathway. J Biol Chem, 1999. 274(30): p. 20745-8. Cerca con Google

88. Lymboussaki, A., et al., Vascular endothelial growth factor (VEGF) and VEGF-C show overlapping binding sites in embryonic endothelia and distinct sites in differentiated adult endothelia. Circ Res, 1999. 85(11): p. 992-9. Cerca con Google

89. Shida, A., et al., Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma. Int J Clin Oncol, 2006. 11(1): p. 38-43. Cerca con Google

90. Su, J.L., et al., The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell, 2006. 9(3): p. 209-23. Cerca con Google

91. Karpanen, T., et al., Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J, 2006. 20(9): p. 1462-72. Cerca con Google

92. Stacker, S.A., et al., Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem, 1999. 274 Cerca con Google

(45): p. 32127-36. Cerca con Google

93. Rocchigiani, M., et al., Human FIGF: cloning, gene structure, and mapping to chromosome Xp22.1 between the PIGA and the GRPR genes. Genomics, 1998. 47(2): p. 207-16. Cerca con Google

94. Karkkainen, M.J., et al., Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol, 2004. 5(1): p. 74-80. Cerca con Google

95. Baldwin, M.E., et al., Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol, 2005. 25(6): p. 2441-9. Cerca con Google

96. Achen, M.G., et al., Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A, 1998. 95(2): p. 548-53. Cerca con Google

97. Thiele, W. and J.P. Sleeman, Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol, 2006. 124(1): p. 224-41. Cerca con Google

98. Iyer, S., et al., The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution. J Biol Chem, 2001. 276(15): p. 12153-61. Cerca con Google

99. Maglione, D., et al., Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A, 1991. 88(20): p. 9267-71. Cerca con Google

100. Grunewald, F.S., et al., Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta, 2010. 1804(3): p. Cerca con Google

567-80. Cerca con Google

101. Parr, C., et al., Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer, 2005. 41(18): p. 2819-27. Cerca con Google

102. Chen, C.N., et al., The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett, 2004. 213(1): p. 73-82. Cerca con Google

103. Zhang, L., et al., Expression of Placenta growth factor (PlGF) in non-small cell lung cancer (NSCLC) and the clinical and prognostic significance. World J Surg Oncol, 2005. 3: p. 68. Cerca con Google

104. Matsumoto, K., et al., Placental growth factor gene expression in human prostate cancer and benign prostate hyperplasia. Anticancer Res, 2003. 23(5A): p. 3767-73. Cerca con Google

105. Feeney, S.A., et al., Role of vascular endothelial growth factor and placental growth factors during retinal vascular development and hyaloid regression. Invest Ophthalmol Vis Cerca con Google

Sci, 2003. 44(2): p. 839-47. Cerca con Google

106. Persico, M.G., V. Vincenti, and T. DiPalma, Structure, expression and receptorbinding properties of placenta growth factor (PlGF). Curr Top Microbiol Immunol, 1999. 237: p. 31-40. Cerca con Google

107. Odorisio, T., et al., The placenta growth factor in skin angiogenesis. J Dermatol Sci, 2006. 41(1): p. 11-9. Cerca con Google

108. Carmeliet, P., et al., Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological Cerca con Google

conditions. Nat Med, 2001. 7(5): p. 575-83. Cerca con Google

109. Meyer, M., et al., A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J, 1999. 18(2): p. 363-74. Cerca con Google

110. de Vries, C., et al., The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science, 1992. 255(5047): p. 989-91. Cerca con Google

111. Waltenberger, J., et al., Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem, 1994. 269(43): p. 26988-95. Cerca con Google

112. Olofsson, B., et al., Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Cerca con Google

Sci U S A, 1998. 95(20): p. 11709-14. Cerca con Google

113. Barleon, B., et al., Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood, 1996. 87(8): p. Cerca con Google

3336-43. Cerca con Google

114. Kendall, R.L. and K.A. Thomas, Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A, 1993. 90 Cerca con Google

(22): p. 10705-9. Cerca con Google

115. Park, J.E., et al., Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. Cerca con Google

J Biol Chem, 1994. 269(41): p. 25646-54. Cerca con Google

116. Sawano, A., et al., The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochem Biophys Res Commun, 1997. 238(2): p. 487-91. Cerca con Google

117. Ito, N., et al., Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules. J Biol Chem, 1998. Cerca con Google

273(36): p. 23410-8. Cerca con Google

118. Takahashi, T., et al., A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J, 2001. 20(11): p. 2768-78. Cerca con Google

119. Kendall, R.L., et al., Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues. J Biol Chem, 1999. 274(10): p. 6453-60. Cerca con Google

120. Autiero, M., et al., Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med, 2003. 9(7): p. 936-43. Cerca con Google

121. Ebos, J.M., et al., A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res, 2004. 2(6): p. 315-26. Cerca con Google

122. Gerber, H.P., et al., Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem, 1997. 272(38): p. 23659-67. Cerca con Google

123. Kaipainen, A., et al., Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A, 1995. 92 Cerca con Google

(8): p. 3566-70. Cerca con Google

124. Pajusola, K., et al., FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res, 1992. 52(20): p. Cerca con Google

5738-43. Cerca con Google

125. Nilsson, I., et al., Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development. FASEB J, 2004. 18(13): p. 1507-15. Cerca con Google

126. Dixelius, J., et al., Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem, 2003. 278(42): p. 40973-9. Cerca con Google

127. Alam, A., et al., Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochem Biophys Res Commun, 2004. 324(2): p. 909-15. Cerca con Google

128. Olsson, A.K., et al., VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol, 2006. 7(5): p. 359-71. Cerca con Google

129. LeCouter, J., et al., Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature, 2001. 412(6850): p. 877-84. Cerca con Google

130. Joubert, F.J. and D.J. Strydom, Snake venom. The amino acid sequence of protein A from Dendroaspis polylepis polylepis (black mamba) venom. Hoppe Seylers Z Physiol Chem, 1980. 361(12): p. 1787-94. Cerca con Google

131. Cheng, M.Y., et al., Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature, 2002. 417(6887): p. 405-10. Cerca con Google

132. Melchiorri, D., et al., The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways. Eur J Neurosci, 2001. 13(9): p. 1694-702. Cerca con Google

133. Wechselberger, C., et al., The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes. FEBS Lett, 1999. 462(1-2): p. 177-81. Cerca con Google

134. LeCouter, J., et al., Mouse endocrine gland-derived vascular endothelial growth factor: a distinct expression pattern from its human ortholog suggests different roles as a regulator of organ-specific angiogenesis. Endocrinology, 2003. 144(6): p. 2606-16. Cerca con Google

135. LeCouter, J., et al., The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells. Proc Natl Acad Sci U S A, 2003. 100(5): p. 2685-90. Cerca con Google

136. LeCouter, J. and N. Ferrara, EG-VEGF and the concept of tissue-specific angiogenic growth factors. Semin Cell Dev Biol, 2002. 13(1): p. 3-8. Cerca con Google

137. Morales, A., et al., Expression and localization of endocrine gland-derived vascular endothelial growth factor (EG-VEGF) in human pancreas and pancreatic adenocarcinoma. J Steroid Biochem Mol Biol, 2007. 107(1-2): p. 37-41. Cerca con Google

138. Abad, J.D., et al., T-cell receptor gene therapy of established tumors in a murine melanoma model. J Immunother, 2008. 31(1): p. 1-6. Cerca con Google

139. Lin, D.C., et al., Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J Biol Chem, 2002. 277(22): p. 19276-80. Cerca con Google

140. Keramidas, M., et al., Mitogenic functions of endocrine gland-derived vascular endothelial growth factor and Bombina variegata 8 on steroidogenic adrenocortical cells. J Endocrinol, 2008. 196(3): p. 473-82. Cerca con Google

141. Weiss, L.M., L.J. Medeiros, and A.L. Vickery, Jr., Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol, 1989. 13(3): p. 202-6. Cerca con Google

142. Macfarlane, D.A., Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl, 1958. 23(3): p. 155-86. Cerca con Google

143. Sullivan, M., M. Boileau, and C.V. Hodges, Adrenal cortical carcinoma. J Urol, 1978. 120(6): p. 660-5. Cerca con Google

144. Unger, N., et al., Immunohistochemical localization of somatostatin receptor subtypes in benign and malignant adrenal tumours. Clin Endocrinol (Oxf), 2008. 68(6): p. 850-7. Cerca con Google

145. Unger, N., et al., Immunohistochemical determination of somatostatin receptor subtypes 1, 2A, 3, 4, and 5 in various adrenal tumors. Endocr Res, 2004. 30(4): p. 931-4. Cerca con Google

146. Pisarek, H., et al., Somatostatin receptors in human adrenal gland tumors-immunohistochemical study. Folia Histochem Cytobiol, 2008. 46(3): p. 345-51. Cerca con Google

147. Sharma, K., Y.C. Patel, and C.B. Srikant, Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol, Cerca con Google

1996. 10(12): p. 1688-96. Cerca con Google

148. Florio, T., Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors. Front Biosci, 2008. 13: p. 822-40. Cerca con Google

149. Florio, T., et al., Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogenactivated Cerca con Google

protein kinase activities. Endocrinology, 2003. 144(4): p. 1574-84. Cerca con Google

150. Hofland, L.J., Somatostatin and somatostatin receptors in Cushing's disease. Mol Cell Endocrinol, 2008. 286(1-2): p. 199-205. Cerca con Google

151. de Bruin, C., et al., Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome. Rev Endocr Metab Disord, 2009. 10(2): p. 91-102. Cerca con Google

152. McDermott, J.H., et al., ACTH-secreting bronchial carcinoid: a diagnostic and therapeutic challenge. Ir J Med Sci, 2008. 177(3): p. 269-72. Cerca con Google

153. Heikkila, P., et al., Expression of vascular endothelial growth factor in human adrenals. Endocr Res, 2000. 26(4): p. 867-71. Cerca con Google

154. Nusslein-Volhard, C. and E. Wieschaus, Mutations affecting segment number and polarity in Drosophila. Nature, 1980. 287(5785): p. 795-801. Cerca con Google

155. McMahon, A.P., P.W. Ingham, and C.J. Tabin, Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol, 2003. 53: p. 1-114. Cerca con Google

156. Nieuwenhuis, E. and C.C. Hui, Hedgehog signaling and congenital malformations. Clin Genet, 2005. 67(3): p. 193-208. Cerca con Google

157. Ingham, P.W. and A.P. McMahon, Hedgehog signaling in animal development: paradigms and principles. Genes Dev, 2001. 15(23): p. 3059-87. Cerca con Google

158. Mill, P., et al., Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev, 2003. 17(2): p. 282-94. Cerca con Google

159. Grachtchouk, M., et al., Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet, 2000. 24(3): p. 216-7. Cerca con Google

160. Nilsson, M., et al., Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A, 2000. 97(7): p. 3438-43. Cerca con Google

161. Mill, P., et al., Shh controls epithelial proliferation via independent pathways that converge on N-Myc. Dev Cell, 2005. 9(2): p. 293-303. Cerca con Google

162. Ulloa, F., N. Itasaki, and J. Briscoe, Inhibitory Gli3 activity negatively regulates Wnt/beta-catenin signaling. Curr Biol, 2007. 17(6): p. 545-50. Cerca con Google

163. Hallikas, O., et al., Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell, 2006. 124(1): p. 47-59. Cerca con Google

164. Wijgerde, M., et al., A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Cerca con Google

Genes Dev, 2002. 16(22): p. 2849-64. Cerca con Google

165. Buttitta, L., et al., Interplays of Gli2 and Gli3 and their requirement in mediating Shhdependent sclerotome induction. Development, 2003. 130(25): p. 6233-43. Cerca con Google

166. Vokes, S.A., et al., Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development, 2007. 134(10): p. 1977-89. Cerca con Google

167. Vokes, S.A., et al., A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev, 2008. 22(19): p. Cerca con Google

2651-63. Cerca con Google

168. Beachy, P.A., S.S. Karhadkar, and D.M. Berman, Tissue repair and stem cell renewal in carcinogenesis. Nature, 2004. 432(7015): p. 324-31. Cerca con Google

169. Karhadkar, S.S., et al., Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 2004. 431(7009): p. 707-12. Cerca con Google

170. Watkins, D.N., et al., Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature, 2003. 422(6929): p. 313-7. Cerca con Google

171. Fendrich, V., et al., Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology, 2008. 135(2): p. 621-31. Cerca con Google

172. Wicking, C., I. Smyth, and A. Bale, The hedgehog signalling pathway in tumorigenesis and development. Oncogene, 1999. 18(55): p. 7844-51. Cerca con Google

173. Lindemann, R.K., Stroma-initiated hedgehog signaling takes center stage in B-cell lymphoma. Cancer Res, 2008. 68(4): p. 961-4. Cerca con Google

174. Ruiz i Altaba, A., C. Mas, and B. Stecca, The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol, 2007. 17(9): p. 438-47. Cerca con Google

175. Yauch, R.L., et al., A paracrine requirement for hedgehog signalling in cancer. Nature, 2008. 455(7211): p. 406-10. Cerca con Google

176. Stamataki, D., et al., A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes Dev, 2005. 19(5): p. 626-41. Cerca con Google

177. Methot, N. and K. Basler, Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell, 1999. 96(6): p. 819-31. Cerca con Google

178. Strigini, M. and S.M. Cohen, A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development, 1997. 124(22): p. 4697-705. Cerca con Google

179. Jia, J., et al., Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature, 2004. 432(7020): p. 1045-50. Cerca con Google

180. Smelkinson, M.G., Q. Zhou, and D. Kalderon, Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. Dev Cell, 2007. 13(4): p. Cerca con Google

481-95. Cerca con Google

181. Cohen, M.M., Jr., The hedgehog signaling network. Am J Med Genet A, 2003. 123A (1): p. 5-28. Cerca con Google

182. King, P.J., L. Guasti, and E. Laufer, Hedgehog signalling in endocrine development and disease. J Endocrinol, 2008. 198(3): p. 439-50. Cerca con Google

183. Bai, C.B., et al., Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development, 2002. 129(20): p. 4753-61. Cerca con Google

184. Kang, S., et al., GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet, 1997. 15(3): p. 266-8. Cerca con Google

185. Chemaitilly, W., et al., Adrenal insufficiency and abnormal genitalia in a 46XX female with Smith-Lemli-Opitz syndrome. Horm Res, 2003. 59(5): p. 254-6. Cerca con Google

186. Andersson, H.C., et al., Adrenal insufficiency in Smith-Lemli-Opitz syndrome. Am J Med Genet, 1999. 82(5): p. 382-4. Cerca con Google

187. Bose, J., L. Grotewold, and U. Ruther, Pallister-Hall syndrome phenotype in mice mutant for Gli3. Hum Mol Genet, 2002. 11(9): p. 1129-35. Cerca con Google

188. Bitgood, M.J. and A.P. McMahon, Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol, 1995. 172(1): p. 126-38. Cerca con Google

189. Soriano, P., Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet, 1999. 21(1): p. 70-1. Cerca con Google

190. Picard, D., Regulation of protein function through expression of chimaeric proteins. Curr Opin Biotechnol, 1994. 5(5): p. 511-5. Cerca con Google

191. Feil, R., et al., Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci U S A, 1996. 93(20): p. 10887-90. Cerca con Google

192. Danielian, P.S., et al., Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol, 1998. 8(24): p. 1323-6. Cerca con Google

193. Feil, R., et al., Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun, 1997. 237(3): p. 752-7. Cerca con Google

194. Indra, A.K., et al., Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER Cerca con Google

(T) and Cre-ER(T2) recombinases. Nucleic Acids Res, 1999. 27(22): p. 4324-7. Cerca con Google

195. Ahn, S. and A.L. Joyner, Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell, 2004. 118(4): p. 505-16. Cerca con Google

196. King, P., A. Paul, and E. Laufer, Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A, 2009. (50): p. 21185-90. Cerca con Google

197. Huang, C.C., et al., Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology, 2010. 151(3): p. 1119-28. Cerca con Google

198. Han, Y.G., et al., Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med, 2009. 15(9): p. 1062-5. Cerca con Google

199. Tang, M., et al., Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons. J Neurosci, 2010. 30(27): p. Cerca con Google

9280-91. Cerca con Google

200. Miyagawa, S., et al., Dosage-dependent hedgehog signals integrated with Wnt/betacatenin signaling regulate external genitalia formation as an appendicular program. Development, 2009. 136(23): p. 3969-78. Cerca con Google

201. Ulloa, F. and E. Marti, Wnt won the war: antagonistic role of Wnt over Shh controls dorso-ventral patterning of the vertebrate neural tube. Dev Dyn, 2010. 239(1): p. 69-76. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record