Sarah Krampitz

Tumor-associated blood vessels differ from normal vessels and proteins present only on tumor vessels may serve as biomarkers or targets for antiangiogenic therapy in cancer. Comparing the transcriptional profiles of blood vascular endothelium from human invasive bladder cancer with normal bladder tissue, we found that the endothelial cell-specific molecule endocan (ESM1) was highly elevated on tumor vessels. Endocan was associated with filopodia of angiogenic endothelial tip cells in invasive bladder cancer. Notably, endocan expression on tumor vessels correlated strongly with staging and invasiveness, predicting a shorter recurrence-free survival time in noninvasive bladder cancers. Both endocan and VEGF-A levels were higher in plasma of patients with invasive bladder cancer than healthy individuals. Mechanistic investigations in cultured blood vascular endothelial cells or transgenic mice revealed that endocan expression was stimulated by VEGF-A through the phosphorylation and activation of VEGFR-2, which was required to promote cell migration and tube formation by VEGF-A. Taken together, our findings suggest that disrupting endocan interaction with VEGFR-2 or VEGF-A could offer a novel rational strategy to inhibit tumor angiogenesis. Furthermore, they suggest that endocan might serve as a useful biomarker to monitor disease progression and the efficacy of VEGF-A-targeting therapies in patients with bladder cancer.

Abstract Tumor-associated blood vessels differ from normal vessels at the morphological and molecular level. Proteins that are only present on tumor vessels may serve as biomarkers and as therapeutic targets for inhibition of angiogenesis in cancer. To identify factors contributed by the tumor-associated endothelium, we performed immuno-laser capture microdissection (i-LCM) of blood vascular endothelial cells in conjunction with transcriptional profiling from surgically harvested cancer and normal matched bladder tissue of five patients with invasive bladder cancer. Comparing the transcriptional profiles of blood vascular endothelium from human invasive bladder cancer and from normal bladder tissue, we found that endocan (endothelial cell-specific molecule-1) was highly elevated on tumor vessels and associated with the filopodia of angiogenic endothelial tip cells in invasive bladder cancer. Notably, endocan expression on tumor vessels strongly correlated with the tumor stage and invasiveness and predicted a shorter recurrence-free survival time in non-invasive bladder cancers. Furthermore, both endocan and VEGF-A levels were significantly higher in plasma of patients with invasive bladder cancer (n=53) compared to healthy individuals (n=60). Using cultured blood vascular endothelial cells and an in vivo transgenic mouse model we found that endocan expression was strongly upregulated by VEGF-A activation of VEGFR-2. RNA interference-mediated knockdown of endocan in cultured blood vascular endothelial cells revealed that endocan was required for the promotion of cell migration and tube formation by VEGF-A. Furthermore, we found that endocan potentiates VEGFR-2 phosphorylation in response to VEGF-A. Therefore, blocking the interaction of endocan with either VEGFR-2 or VEGF-A might represent a promising approach for inhibiting tumor angiogenesis. Endocan might also serve as a novel biomarker for monitoring disease progression and the efficacy of VEGF-A-targeting therapies in patients with bladder cancer. Citation Format: Filip Roudnicky, Cedric Poyet, Peter J. Wild, Sarah Krampitz, Fabrizia Negrini, Reto Huggenberger, Anja Rogler, Robert Stöhr, Arndt Hartmann, Maurizio Provenzano, Vivianne I. Otto, Michael Detmar. Endocan is upregulated on tumor vessels in invasive bladder cancer and mediates VEGF-A-induced angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3893. doi:10.1158/1538-7445.AM2013-3893

You have accessJournal of UrologyBladder Cancer: Basic Research (III)1 Apr 20131124 ENDOCAN IS UPREGULATED ON TUMOR VESSELS IN MUSCLE-INVASIVE BLADDER CANCER AND MEDIATES VEGF-A INDUCED ANGIOGENESIS Cédric Poyet, Filip Roudnicky, Peter Wild, Sarah Krampitz, Fabrizia Negrini, Reto Huggenberger, Anja Rogler, Arndt Hartmann, Tullio Sulser, Maurizio Provenzano, Vivianne I. Otto, and Michael Detmar Cédric PoyetCédric Poyet Zürich, Switzerland More articles by this author , Filip RoudnickyFilip Roudnicky Zürich, Switzerland More articles by this author , Peter WildPeter Wild Zürich, Switzerland More articles by this author , Sarah KrampitzSarah Krampitz Zürich, Switzerland More articles by this author , Fabrizia NegriniFabrizia Negrini Zürich, Switzerland More articles by this author , Reto HuggenbergerReto Huggenberger Zürich, Switzerland More articles by this author , Anja RoglerAnja Rogler Erlangen, Germany More articles by this author , Arndt HartmannArndt Hartmann Erlangen, Germany More articles by this author , Tullio SulserTullio Sulser Zürich, Switzerland More articles by this author , Maurizio ProvenzanoMaurizio Provenzano Zürich, Switzerland More articles by this author , Vivianne I. OttoVivianne I. Otto Zürich, Switzerland More articles by this author , and Michael DetmarMichael Detmar Zürich, Switzerland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.739AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Death from muscle invasive bladder cancer (MIBC) results mostly from metastatic disease. Tumor angiogenesis provides the supply of oxygen and nutrients to the proliferating urothelial tumor cells. Tumor-associated blood vessels 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 In order to identify factors contributed by tumor-associated endothelium, we have performed immuno-laser capture microdissection (LCM) of blood vascular endothelial cells in conjunction with transcriptional profiling. RNA was extracted from isolated vascular blood endothelial cells. Transcriptional profiles were obtained. Cultured blood vascular endothelial cells (BECs) were used. In addition tissue microarray and immunohistochemistry were performed. RESULTS Comparing the transcriptional profiles of human muscle invasive bladder cancer (MIBC)-associated blood vascular endothelium and of normal bladder vascular endothelium, we found that endocan (endothelial cell-specific molecule-1) was highly elevated on tumor vessels (1'000- to 100'000-fold). This upregulation was confirmed by RT-qPCR and immunohistochemistry. Notably, endocan expression on tumor vessels strongly correlated with the tumor stage and invasiveness and predicted a shorter recurrence-free survival time in non-invasive bladder cancers (Tissue microarray consisting of 143 samples of non-invasive (N= 89) and invasive bladder cancer (N= 54) patients). In addition, endocan and VEGF-A levels were significantly higher in plasma of patients with invasive bladder cancer (n=53) compared to healthy individuals (n=60). In cultured BECs endocan expression is strongly upregulated by VEGF-A activation of VEGFR-2. RNA interference-mediated knockdown of endocan in cultured BECs revealed that endocan was required for the promotion of cell migration and tube formation by VEGF-A. CONCLUSIONS Our study provides evidence that endocan is upregulated on bladder cancer-associated blood vessels. Endocan might serve as a biomarker for the monitoring disease progression and for the therapeutic effectiveness of VEGF-A-targeting therapies. Moreover it also indicates that endocan plays crucial roles in supporting and promoting VEGF-A-induced tumor angiogenesis. Blocking the interaction of endocan to either VEGFR-2 or VEGF-A might represent a promising approach for inhibiting tumor angiogenesis. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e459 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cédric Poyet Zürich, Switzerland More articles by this author Filip Roudnicky Zürich, Switzerland More articles by this author Peter Wild Zürich, Switzerland More articles by this author Sarah Krampitz Zürich, Switzerland More articles by this author Fabrizia Negrini Zürich, Switzerland More articles by this author Reto Huggenberger Zürich, Switzerland More articles by this author Anja Rogler Erlangen, Germany More articles by this author Arndt Hartmann Erlangen, Germany More articles by this author Tullio Sulser Zürich, Switzerland More articles by this author Maurizio Provenzano Zürich, Switzerland More articles by this author Vivianne I. Otto Zürich, Switzerland More articles by this author Michael Detmar Zürich, Switzerland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...