Dhugal F. Bedford

Abstract 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 γ (PPARγ), 15-deoxy-Δ12,14-prostaglandin J2, troglitazone, and rosiglitazone increased PPARγ and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARγ ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-Δ12,14-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARγ ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

Disturbances of the ratio between angiogenic inducers and inhibitors in tumor microenvironment are the driving force behind angiogenic switch critical for tumor progression. Angiogenic inhibitors may vary depending on organismal age and the tissue of origin. We showed that alpha(1)-antitrypsin (AAT), a serine protease inhibitor (serpin) is an inhibitor of angiogenesis, which induced apoptosis and inhibited chemotaxis of endothelial cells. S- and Z-type mutations that cause abnormal folding and defective serpin activity abrogated AAT antiangiogenic activity. Removal of the C-terminal reactive site loop had no effect on its angiostatic activity. Both native AAT and AAT truncated on C-terminus (AATDelta) inhibited neovascularization in the rat cornea and delayed the growth of subcutaneous tumors in mice. Treatment with native AAT and truncated AATDelta, but not control vehicle reduced tumor microvessel density, while increasing apoptosis within tumor endothelium. Comparative analysis of the human tumors and normal tissues of origin showed correlation between reduced local alpha(1)-antitrypsin expression and more aggressive tumor growth.

You have accessJournal of UrologyModerated Poster, Monday, May 23, 2005, 1:00 - 3:00 pm1 Apr 2005814: Prediction of Advanced Prostate Cancer Using Biopsy Parameters: The Contribution of Tumor Percentage, Volume and the Number of Positive Biopsy Cores Misop Han, Michelle R. Pattison, Sheila A. Hawkins, Xiaoying Yu, Dhugal F. Bedford, Linning Liao, and William J. Catalona Misop HanMisop Han More articles by this author , Michelle R. PattisonMichelle R. Pattison More articles by this author , Sheila A. HawkinsSheila A. Hawkins More articles by this author , Xiaoying YuXiaoying Yu More articles by this author , Dhugal F. BedfordDhugal F. Bedford More articles by this author , Linning LiaoLinning Liao More articles by this author , and William J. CatalonaWilliam J. Catalona More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)34983-8AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "814: Prediction of Advanced Prostate Cancer Using Biopsy Parameters: The Contribution of Tumor Percentage, Volume and the Number of Positive Biopsy Cores." The Journal of Urology, 173(4S), pp. 220–221 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 220-221 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Misop Han More articles by this author Michelle R. Pattison More articles by this author Sheila A. Hawkins More articles by this author Xiaoying Yu More articles by this author Dhugal F. Bedford More articles by this author Linning Liao More articles by this author William J. Catalona More articles by this author Expand All Advertisement PDF DownloadLoading ...

bluntly dissected as deep as possible and then totally removed; the defect is filled with surgicel and sutured. Laparoscopic major polar resection: 41 years old gentleman with bilateral tumors because of von Hippel-Lindal disease and tumor greater than 5 em in the lower pole extending into the hilum; the ureter should be widely mobilized to avoid its injury throughout the procedure; intracorporeal ultrasound is used; a satinsky clamp is used to en bloc control; the renal parenchyma is incised as deep as it is necessary; hemostasis is obtained aposing the renal margins with stiches RESULTS: Seven laparoscopic partial nephrectomies with tumors in the hilum were performed from November/2000 to September/04 out of 40 cases. Average OR time was 161 minutes, average warm ischemia time was 23,7 minutes, and average hospital stay was 2, 7 days. One transient fever occurred and one patient needed postoperative transfusion. One case had microscopic positive margin with no recurrence up to 10 months foiiow up.