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Carcinogenesis Advance Access originally published online on February 23, 2009
Carcinogenesis 2009 30(5):851-860; doi:10.1093/carcin/bgp052
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Interferon-{alpha} counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer

Luca Persano1, Lidia Moserle1, Giovanni Esposito2, Vincenzo Bronte2, Vito Barbieri1, Massimo Iafrate3, Marina P. Gardiman4, Patrizia Larghero5, Ulrich Pfeffer5, Elisabeth Naschberger6, Michael Stürzl6, Stefano Indraccolo2,* and Alberto Amadori1,2

1 Oncology Section, Department of Oncology and Surgical Sciences, University of Padova, Padova I-35128, Italy
2 Istituto Oncologico Veneto-IRCCS, Padova I-35128, Italy
3 Urology Section, Department of Oncology and Surgical Sciences, University of Padova, Padova I-35128, Italy
4 Pathology Unit, Azienda Ospedaliera, Padova I-35128, Italy
5 Functional Genomics, National Cancer Research Institute, Genova I-16132, Italy
6 Department of Surgery, Division of Molecular and Experimental Surgery, Erlangen D-91054, Germany

* To whom correspondence should be addressed. Tel: +39 0498215875; Fax +30 0498072854; Email: stefano.indraccolo{at}unipd.it

Interferon (IFN)-{alpha} is a cytokine with marked therapeutic activity in transplantable tumor models, that is in part due to angiogenesis inhibition. Aim of this study was to investigate the effects of IFN-{alpha} during the early phases of tumor development in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. To provide sustained IFN-{alpha} production, TRAMP mice were injected intraperitoneally with lentiviral vectors. IFN-{alpha} administration resulted in rapid and protracted upregulation of IFN-{alpha}-regulated genes associated with antiangiogenic and antiproliferative functions in the prostate of TRAMP mice, including guanylate-binding protein 1 (GBP-1), IFI204 and CXCL10-11. These transcriptional changes were accompanied by effects on the tumor vasculature, including significant reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, without induction of tumor necrosis. Intriguingly, GBP-1 and myxovirus resistance A, two IFN-regulated proteins, were found expressed in ~40% of human prostate cancer samples analyzed, suggesting expression of endogenous IFN-{alpha}. Overall, these findings demonstrate that IFN-{alpha} is able to counteract the angiogenic switch and impairs tumor cell proliferation in preinvasive lesions. Since the angiogenic switch also marks progression of human prostatic cancer, these results highlight the potential of angiogenesis inhibitors for the development of chemoprevention strategies in high-risk individuals.

Abbreviations: bFGF, basic fibroblast growth factor; EC, endothelial cell; EGFP, enhanced green fluorescent protein; GBP-1, guanylate-binding protein 1; hGBP-1, human guanylate-binding protein 1; IFN, interferon; LV, lentiviral vectors; mAb, monoclonal antibody; MxA, myxovirus resistance A; PCR, polymerase chain reaction; PIN, prostatic intraepithelial neoplasia; TRAMP, transgenic adenocarcinoma of the mouse prostate; VEGF, vascular endothelial growth factor

Received October 21, 2008; revised February 3, 2009; accepted February 4, 2009.


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