MP68-09 INSULIN RECEPTOR IS OVEREXPRESSED IN TUMOR BLOOD VESSELS AND PREDICTS WORSE OUTCOME IN BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research IV1 Apr 2015MP68-09 INSULIN RECEPTOR IS OVEREXPRESSED IN TUMOR BLOOD VESSELS AND PREDICTS WORSE OUTCOME IN BLADDER CANCER Cédric Poyet, Filip Roudnicky, Peter Wild, Lothar Dieterich, Lorenz Buser, Chien Ho, Tullio Sulser, Vivianne Otto, and Michael Detmar Cédric PoyetCédric Poyet More articles by this author , Filip RoudnickyFilip Roudnicky More articles by this author , Peter WildPeter Wild More articles by this author , Lothar DieterichLothar Dieterich More articles by this author , Lorenz BuserLorenz Buser More articles by this author , Chien HoChien Ho More articles by this author , Tullio SulserTullio Sulser More articles by this author , Vivianne OttoVivianne Otto More articles by this author , and Michael DetmarMichael Detmar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2471AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Invasive bladder cancer (IBC) often leads to a metastatic and lethal disease, whereas non-invasive bladder cancer (NIBC) is characterized by high recurrence rates. Tumor angiogenesis provides the supply of oxygen and nutrients to the proliferating urothelial tumor cells. Tumor–associated blood vessels are believed to differ from normal vessels at the morphological and molecular level. Proteins that are only present on tumor vessels may thus serve as biomarkers and as therapeutic targets for inhibition of angiogenesis in bladder cancer. METHODS we have performed immuno-laser capture microdissection of blood vascular endothelial cells in conjunction with transcriptional profiling. RNA was extracted from isolated vascular blood endothelial Cultured blood vascular endothelial cells (BECs) were used. In addition tissue microarray and immunohistochemistry were performed. RESULTS Comparing the mRNA levels of insulin receptor of human IBC-associated BECs and of normal bladder BECs from 5 patients, we found that insulin receptor (INSR) was highly elevated on tumor vessels. This upregulation was confirmed at the protein level by immunohistochemical staining. Notably, strong INSR expression on bladder cancer-associated BECs was associated with significantly reduced progression-free survival (PFS) and significantly reduced overall survival (OS) in patients with IBC after radical cystectomy (n=66). Furthermore, strong INSR expression was associated with shorter recurrence-free survival (RFS) in patients with NIBC (n=90). In addition, several other carcinomas, sarcomas and lymphomas showed high level INSR expression of the blood vasculature as detected by immunohistochemical staining. To elucidate the mechanisms of INSR regulation, primary human dermal blood vascular endothelial cells (BECs) were incubated with growth/inflammatory factors (VEGF-A, FGF-2, HGF, TNF-α, TGF-β, IGF-1, IGF-2; all 20 ng/ml) or metabolic substrates/conditions (glucose – 30 mM, insulin - 10 μM, acidosis – pH 6.6, lactate – 10 mM, hypoxia – 1% O2) for 24 h. Hypoxia significantly upregulated INSR in BECs in vitro. CONCLUSIONS Our study provides evidence that INSR is upregulated on bladder cancer-associated blood vessels and is of prognostic relevance in bladder cancer. Moreover, it also indicates that INSR is upregulated by hypoxia and could have a role in tumor angiogenesis. The detailed role of INSR in tumor angiogenesis must be elucidated in future studies. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e861 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cédric Poyet More articles by this author Filip Roudnicky More articles by this author Peter Wild More articles by this author Lothar Dieterich More articles by this author Lorenz Buser More articles by this author Chien Ho More articles by this author Tullio Sulser More articles by this author Vivianne Otto More articles by this author Michael Detmar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...