Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas

Abstract

Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors a and b as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor a and 13 cases (59%) showing high staining scores for PDGF receptor b. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases). PDGFRB amplification status and PDGF receptor b protein expression scores were significantly correlated (P ¼ 0.01, Spearman). Expression status of PDGF receptor a or PDGF receptor b was not significantly associated with progressionfree survival. To conclude, expression and amplification of PDGF receptors, particularly PDGF receptor b, are frequent in choroid plexus carcinomas, providing a first rationale for the development of treatments targeting PDGF receptor signaling in these rare malignant pediatric tumors.

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

“…In contrast to PDGF receptors, 14,30 reports of c-Abl expression in central nervous system tumors remain sparse. It has been demonstrated that tyrosine kinases play a functional role in a variety of pediatric neoplasms, [11][12][13][14][15] and the few studies that have evaluated c-Abl expression in brain tumors encountered low expression levels in only a fraction of tumors. For example, Haberler et al observed focal c-Abl expression in only 7 of 101 glioblastomas.…”

“…Previous data suggest that tyrosine kinase receptor signaling may play a role in the biology of more common pediatric solid tumors, such as medulloblastomas, ependymomas, and choroid plexus tumors, and in Ewing sarcomas and neuroblastomas. [9][10][11][12][13][14][15][16] Imatinib, a tyrosine kinase inhibitor directed against c-Abl, c-Kit and platelet-derived growth factor (PDGF) receptor subtypes a and b, 17 reportedly is tolerated relatively well in children. 18,19 Because it has been demonstrated that imatinib inhibits proliferation of the rhabdoid tumor cell line BT12, 20 our objective was to investigate the expression and functional role of tyrosine kinases targeted by imatinib in rhabdoid tumors.…”

Platelet-Derived Growth Factor Receptor Expression and Activation in Choroid Plexus Tumors

“…Extending previous observations, 8 the majority of choroid plexus tumors showed protein expression of PDGF re- ceptor subtypes ␣ and ␤. Whereas PDGF receptor subtypes ␣ and ␤ were both expressed in choroid plexus papillomas, atypical choroid plexus papillomas, and choroid plexus carcinomas, increased receptor phosphorylation was restricted to PDGF receptor ␤ and only observed in choroid plexus carcinomas, suggesting a role of PDGF receptor ␤ activation in the biology of choroid plexus carcinomas.…”

“…The signal was developed using diaminobenzidine as a substrate (SK4100, Vector Laboratories) and counterstained with hematoxylin. PDGF receptor staining was evaluated semiquantitatively as described previously 8 by scoring the percentage of stained cells [0 (absent), 1 (Ͻ10%), 2 (10 to 50%), 3 (51 to 80%), 4 (81 to 100%)], as well as staining intensity [0 (absent), 1 (weak), 2 (distinct), 3 (strong)] across the whole sections. Both scores were then multiplied to give a maximal staining score of twelve.…”

“…5 PDGF receptor signaling can be blocked by imatinib (gleevec), a tyrosine kinase inhibitor showing high specificity for PDGF receptors, c-kit and c-abl 6 and has been shown to be generally well tolerated in children. 7 The observation that PDGF receptors ␣ and ␤ are expressed in choroid plexus carcinomas, 8 prompted us to examine PDGF receptor activation in choroid plexus tumors as well as its functional consequences. In situ proximity ligation assay (in situ PLA) is a new sensitive and specific method that has been successfully used for the visualization of PDGF ␤ receptor phosphorylation status in cells and fresh-frozen tissues.…”