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Persano, Luca (2009) Stratergie di terapia anti-angiogenica con IFN-ALFA in un modello di neoplasia prostatica spontanea. [Ph.D. thesis]

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Abstract (english)

Interferon-alpha (IFN-alpha) is the prototype of anti-angiogenic cytokines with recognized therapeutic activity in transplantable and orthotopic tumors, and also in prostatic cancer models. This activity has been mainly attributed to indirect effects, such as the down-regulation of pro-angiogenic factors, or direct effects on proliferation and motility of endothelial cells. Aim of this study was to investigate the effects of IFN-alpha on the angiogenic switch occurring during the early phases of tumor development in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model in which tumorigenesis is driven by an androgen-regulated early gene (T/t antigen) of SV40. To provide sustained IFN-alpha production, TRAMP mice were injected i.p. with IFN-alpha-producing lentiviral vectors, followed by analysis of the IFN-mediated transcriptional and biologic effects.
In the prostate of TRAMP mice, IFN-alpha administration resulted in sustained up-regulation of IFN-alpha-regulated genes endowed with anti-angiogenic and anti-proliferative functions, including guanylate binding protein 1 (GBP-1), IFI16 protein and CXCL10-11; since the levels of these transcripts increased at early time points following treatment, they could be primary mediators of the biologic effects of IFN-alpha. These transcriptional changes were accompanied by effects on the tumor vasculature, including reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, whereas tumor cell apoptosis was unchanged. Intriguingly, a subgroup of human prostatic tumors analyzed (15 out of 31) disclosed GBP-1 protein expression, and this correlated with the expression of another IFN-regulated protein, MxA, thus hinting at endogenous IFN-alpha in a subset of prostate cancer patients.
Overall, our findings demonstrate that IFN-alpha is able to counteract the angiogenic switch and impair tumor cell proliferation during the early phases of prostatic cancer progression. The detection of GBP-1 and MxA expression in clinical samples of prostatic cancer may identify a tumor subset with distinct biological features.

Abstract (italian)

L’interferone alfa (IFN-alfa) è il prototipo delle citochine con effetto anti-angiogenico, di cui sono noti gli effetti terapeutici in numerosi modelli tumorali. Questa azione è stata attribuita principalmente ad effetti indiretti, come l’inibizione della produzione di fattori pro-angiogenici da parte delle cellule tumorali ed anche a effetti diretti di IFN-alfa sulla proliferazione e motilità delle cellule endoteliali. Lo scopo di questo lavoro è stato di investigare quali fossero gli effetti del trattamento con IFN-alfa sul processo angiogenico che viene indotto dalle cellule cancerose durante le prime fasi della progressione tumorale. A tal fine abbiamo utilizzato il modello del topo TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) in cui la cancerogenesi è guidata dall’espressione androgeno-regolata degli antigeni T/t di SV40. Per ottenere una produzione sostenuta di IFN-alfa, i topi TRAMP sono stati inoculati per via intraperitoneale con vettori lentivirali producenti IFN-alfa, e successivamente è seguita la valutazione degli effetti trascrizionali e biologici.
La somministrazione di IFN-alfa ha provocato una regolazione in senso positivo di trascritti coinvolti nell’inibizione dell’angiogenesi e della proliferazione cellulare quali GBP-1, IFI16 e CXCL10-11; poiché i livelli di questi trascritti sono stati riscontrati elevati già dalle prime fasi dopo il trattamento, potrebbero essere mediatori degli effetti biologici dell’IFN-alfa. A questi effetti trascrizionali si accompagnano gli effetti sulla vascolatura tumorale, quali la riduzione della densità vascolare intraduttale e l’aumento della maturità dei vasi, associati ad una marcata inibizione della proliferazione delle cellule tumorali, senza peraltro influenzare i livelli di apoptosi. Alla luce di questi risultati abbiamo voluto investigare se anche nel carcinoma prostatico umano ci potessero essere evidenze di espressione di IFN-alfa endogeno. La valutazione immunoistochimica di una serie di tumori prostatici umani ha evidenziato come una parte di questi (15/31) esprimano la proteina GBP-1 e che esiste una correlazione con un’altra proteina indotta da IFN-alfa quale MxA, indicando come in un sottogruppo di pazienti con carcinoma prostatico vi sia una produzione endogena di IFN-alfa.
In sintesi, questi risultati indicano che l’IFN-alfa è in grado di inibire il processo angiogenico e la proliferazione cellulare durante le prime fasi della tumorigenesi prostatica. L’espressione di GBP-1 e MxA in campioni clinici potrebbe identificare un sottogruppo di pazienti con peculiari caratteristiche biologiche.

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EPrint type:Ph.D. thesis
Tutor:Amadori, Alberto
Ph.D. course:Ciclo 21 > Corsi per il 21simo ciclo > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:29 January 2009
Anno di Pubblicazione:January 2009
Key Words:carcinoma prostatico, modello TRAMP, interferone, angiogenesi, GBP-1
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Oncologiche e Chirurgiche
Codice ID:1706
Depositato il:29 Jan 2009
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