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Angiogenesis, Metastasis, and the Cellular Microenvironment

Peroxisome Proliferator-Activated Receptor Ligands Improve the Antitumor Efficacy of Thrombospondin Peptide ABT510¹

Departments of ¹ Urology and ² Microbiology and Immunology and ³ Bioinformatics Core, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois; ⁴ Department of Urology, Loyola University Medical Center, Maywood, Illinois; ⁵ Department of Urology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; and ⁶ Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Olga V. Volpert, Department of Urology, Northwestern University Feinberg School of Medicine, 303 East Superior Street, Tarry 16-761, Chicago, IL 60611. Phone: 312-503-5934; Fax: 312-908-7275. E-mail: olgavolp{at}northwestern.edu

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor (PPAR), 15-deoxy-^12,14-prostaglandin J2, troglitazone, and rosiglitazone increased PPAR and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPAR ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-^12,14-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPAR ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

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