This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dickson, P. V. Articles by Davidoff, A. M. Search for Related Content PubMed PubMed Citation Articles by Dickson, P. V. Articles by Davidoff, A. M.

---

Angiogenesis, Metastasis, and the Cellular Microenvironment

Continuous Delivery of IFN-ß Promotes Sustained Maturation of Intratumoral Vasculature

Departments of ¹ Surgery, ² Radiological Sciences, ³ Developmental Neurobiology, ⁴ Pharmaceutical Sciences, and ⁵ Oncology, St. Jude Children's Research Hospital; Departments of ⁶ Surgery, ⁷ Bioimaging, and ⁸ Pathology, University of Tennessee College of Medicine, Memphis, Tennessee; and ⁹ Department of Hematology, University College London, London, United Kingdom

Requests for reprints: Andrew M. Davidoff, Department of Surgery, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: 901-495-4060; Fax: 901-495-2176. E-mail: andrew.davidoff{at}stjude.org

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-ß on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-ß delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-ß was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-ß–mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling—continuous delivery of IFN-ß. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy. (Mol Cancer Res 2007;5(6):531–42)