ABSTRACT
Chondrosarcomas represent 20% of all primary bone sarcomas, and many studies have attempted to unravel molecular targets for future development of new therapies. The aim of this study was to investigate the expression/activation of PDGFRalpha, PDGFRbeta and KIT receptor tyrosine kinases (RTKs) as potential therapeutic targets in conventional central primary chondrosarcomas (CCS). The expression of PDGFRalpha, PDGFRbeta and KIT RTKs was detected in 16 CCSs using immunohistochemistry (IHC), and their level of expression and activation status were analysed by immunoprecipitation and western blot experiments. PDGFRalpha, PDGFRbeta and KIT cDNAs were screened to verify the presence of activating mutations and the presence of the cognate ligands was analysed by means of RT-PCR. RTK gene amplification was further studied by means of fluorescence in situ hybridization (FISH) analysis. The immunophenotyping and biochemical analyses showed that the CCSs co-expressed PDGFRalpha and PDGFRbeta, with the latter showing definitively greater protein expression and phosphorylation levels. PDGFRbeta was expressed but not activated in control healthy joint cartilage, in line with no PDGFB detection. Conversely, the KIT gene product did not seem to play a relevant role. These findings, in the absence of activating mutations or an abnormal genomic profile and the presence of PDGFA and PDGFB expression, are consistent with an autocrine/paracrine loop activation of the corresponding receptors. The CCS gene profile described here offers a rationale for the use of RTK inhibitors alone or in combination with chemotherapy, and supports further investigation of RTKs and their downstream signals.
Subject(s)
Bone Neoplasms/metabolism , Chondrosarcoma/metabolism , Neoplasm Proteins/metabolism , Bone Neoplasms/genetics , Chondrosarcoma/genetics , Gene Expression Profiling/methods , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Ligands , Neoplasm Proteins/genetics , Phosphorylation , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Receptor, Platelet-Derived Growth Factor beta/genetics , Receptor, Platelet-Derived Growth Factor beta/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methodsABSTRACT
AIMS: To describe a tumour with morphological and immunophenotypic characteristics of epithelioid variant of pleomorphic liposarcoma. Pleomorphic liposarcoma is a very rare variant of liposarcoma defined morphologically by the presence of pleomorphic lipoblasts showing peculiar epithelial-like features that can be confused with primary or metastatic carcinoma. METHODS AND RESULTS: Molecular analysis demonstrated for the first time the presence of FUS-CHOP transcript in this liposarcoma variant. Microarray analysis revealed a gene expression profile related to a more aggressive tumour type when compared with other myxoid/round cell liposarcomas. CONCLUSIONS: The present data show that the epithelioid variant of pleomorphic liposarcoma represents a further variant of myxoid liposarcoma sharing the FUS-CHOP fusion transcript but carrying a distinct expression profile, in keeping with its aggressive clinical course.
