Abstract 3797: Regulation and function of the mucin-like glycoprotein podoplanin in glioma.

Abstract Podoplanin (PDPN) is a mucin like type-1 transmembrane protein consisting of 162 amino acids, which comprises a highly glycosylated extracellular domain and a nine amino acid intracellular domain. The specific expression of PDPN on lymphatic but not on blood vascular endothelial cells has established application as a histological marker for lymphangiogenesis and lymphatic vessels in different species. PDPN is highly expressed in tumors of different origin, including squamous cell cancers, germinal neoplasia and tumors of the central nervous system. Recently, we found strong overexpression of PDPN in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). Regulation of PDPN expression involves increased PI3 kinase activation, subsequent activation of protein kinaseB/Akt and the downstream transcription factor AP-1. Activation of this pathway is mediated by loss of PTEN function, consistently, mice lacking Pten exhibit elevated Pdpn protein levels in the subventricular zone of the brain tissue. Additionally, PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. In patients high expression of PDPN is associated with poor prognosis. Silencing of PDPN results in a decrease in proliferation, migration and invasion of glioma cell lines in vitro and slows down the migration in orthotopic brain slices. Consistently, tumor formation after injection of PDPN knock-down cells into SCID mice is significantly reduced compared to tumors after injection of parental cells. These data highlight a functional role of PDPN in glioma progression and suggest targeting of PDPN expression as a promising strategy for the treatment of patients with primary GB. Citation Format: Heike Peterziel, Julia Müller, Danner Andreas, Sebastian Barbus, Haikun Liu, Philipp Pfenning, Patrick N. Harter, Michel Mittelbronn, Wolfgang Wick, Günther Schuetz, Bernhard Radlwimmer, Peter Lichter, Jochen Hess, Peter Angel. Regulation and function of the mucin-like glycoprotein podoplanin in glioma. [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 3797. doi:10.1158/1538-7445.AM2013-3797