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Platelet-derived growth factor receptor expression and activation in choroid plexus tumors.

ABSTRACT: Choroid plexus tumors are intraventricular neoplasms predominantly affecting young children. In contrast to choroid plexus papillomas, choroid plexus carcinomas progress frequently, necessitating the development of adjuvant treatment concepts. Platelet derived growth factor (PDGF) signaling has been shown to support growth in a variety of tumors. The finding of PDGF receptor expression in choroid plexus tumors prompted us to elucidate PDGF receptor activation state using a novel method, in situ proximity ligation assay, on formalin-fixed, paraffin-embedded, archival samples of 19 choroid plexus tumors. As assessed by in situ proximity ligation assay, the proportion of phosphorylated PDGF receptor alpha was low in choroid plexus papillomas and choroid plexus carcinomas, whereas phosphorylated PDGF receptor beta was found to be significantly higher in choroid plexus carcinomas. In the immortalized choroid plexus epithelial cell line Z310 expressing PDGF receptor beta, PDGF-BB exhibited a time- and dose-dependent proliferative response, which was significantly attenuated by imatinib (gleevec). In conclusion, our findings suggest that PDGF receptor beta is functionally involved in the biology of choroid plexus tumors and may represent a molecular target for therapy. In addition, this study demonstrates the feasibility and usefulness of in situ proximity ligation assay for monitoring receptor tyrosine kinase activation in formalin-fixed, paraffin-embedded, archival tissues.

SUBMITTER: Koos B

PROVIDER: S-EPMC2751559 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Platelet-derived growth factor receptor expression and activation in choroid plexus tumors.

Koos Björn B Paulsson Janna J Jarvius Malin M Sanchez Betzabe Chavez BC Wrede Brigitte B Mertsch Sonja S Jeibmann Astrid A Kruse Anne A Peters Ove O Wolff Johannes E A JE Galla Hans-Joachim HJ Söderberg Ola O Paulus Werner W Ostman Arne A Hasselblatt Martin M

The American journal of pathology 20090828 4

Choroid plexus tumors are intraventricular neoplasms predominantly affecting young children. In contrast to choroid plexus papillomas, choroid plexus carcinomas progress frequently, necessitating the development of adjuvant treatment concepts. Platelet derived growth factor (PDGF) signaling has been shown to support growth in a variety of tumors. The finding of PDGF receptor expression in choroid plexus tumors prompted us to elucidate PDGF receptor activation state using a novel method, in situ ...[more]

PMID: 19717644

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Project description:Although the importance of platelet-derived growth factor receptor (PDGFR)-? signaling during normal alveogenesis is known, it is unclear whether this signaling pathway can regulate realveolarization in the adult lung. During alveolar development, PDGFR-?-expressing cells induce ? smooth muscle actin (?-SMA) and differentiate to interstitial myofibroblasts. Fibroblast growth factor (FGF) signaling regulates myofibroblast differentiation during alveolarization, whereas peroxisome proliferator-activated receptor (PPAR)-? activation antagonizes myofibroblast differentiation in lung fibrosis. Using left lung pneumonectomy, the roles of FGF and PPAR-? signaling in differentiation of myofibroblasts from PDGFR-?-positive precursors during compensatory lung growth were assessed. FGF receptor (FGFR) signaling was inhibited by conditionally activating a soluble dominant-negative FGFR2 transgene. PPAR-? signaling was activated by administration of rosiglitazone. Changes in ?-SMA and PDGFR-? protein expression were assessed in PDGFR-?-green fluorescent protein (GFP) reporter mice using immunohistochemistry, flow cytometry, and real-time PCR. Immunohistochemistry and flow cytometry demonstrated that the cell ratio and expression levels of PDGFR-?-GFP changed dynamically during alveolar regeneration and that ?-SMA expression was induced in a subset of PDGFR-?-GFP cells. Expression of a dominant-negative FGFR2 and administration of rosiglitazone inhibited induction of ?-SMA in PDGFR-?-positive fibroblasts and formation of new septae. Changes in gene expression of epithelial and mesenchymal signaling molecules were assessed after left lobe pneumonectomy, and results demonstrated that inhibition of FGFR2 signaling and increase in PPAR-? signaling altered the expression of Shh, FGF, Wnt, and Bmp4, genes that are also important for epithelial-mesenchymal crosstalk during early lung development. Our data demonstrate for the first time that a comparable epithelial-mesenchymal crosstalk regulates fibroblast phenotypes during alveolar septation.

Dataset Information

Platelet-derived growth factor receptor expression and activation in choroid plexus tumors.

Publications

Platelet-derived growth factor receptor expression and activation in choroid plexus tumors.

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