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Abstract
The aim of this study was to analyze receptor tyrosine kinases (RTK) and their downstream signaling activation profile in myxoid liposarcomas (MLS) by investigating 14 molecularly profiled tumors: 7 naive and 7 treated with conventional chemotherapy/radiotherapy or the new drug trabectedin. Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens were analyzed using biochemical, molecular, and molecular/cytogenetic approaches, complemented by immunohistochemistry and confocal microscopy. In the absence of any RTK and downstream effector deregulation, the naive cases revealed epidermal growth factor receptor, platelet-derived growth factor receptor B, RET, and MET activation sustained by autocrine/paracrine loops, and RTK cross-talk as a result of heterodimerization. Interestingly, RET and MET activation seems to play a major role in the pathogenesis of MLS by involving different targets through different mechanisms. RET activation (which may activate MET) involves the tumoral vascular component by means of RET/MET cross-talk and VEGFA (vascular endothelial growth factor A)/GFRalpha3 (glial cell-derived neurotrophic factor family receptor alpha3)/artemin-mediated signaling as revealed by VEGF receptor 2/RET coimmunoprecipitation. MET activation involves the cellular tumor component by means of a direct ligand-dependent loop and indirect GFRalpha3 (RET coreceptor)/artemin-mediated signaling. About downstream signaling, the association of AKT activation with the round cell variant is interesting. No relevant changes in the original RTK activation profiles were observed in the posttreatment cases, a finding that is in keeping with the nontargeted treatments used. These findings highlight the particular cell-specific activation profile of RET/GFRalpha3 and MET in MLS, and the close correlation between AKT activation and the round cell variant, thus opening up new therapeutic perspectives for MET/AKT inhibitors and antagonistic small molecules binding GFRalpha3.
Highlights
The diagnoses were confirmed by means of fluorescence in situ hybridization (FISH) analysis of fixed material, which revealed the presence of t(12:16), and by reverse transcription-PCR (RT-PCR) searching for the transcript type in cryopreserved tissue checked by H&E-stained frozen section [2, 3]
Immunoprecipitation/Western blotting was used to extend the analysis to all seven cases, concentrating on platelet-derived growth factor receptor B (PDGFRB) and epidermal growth factor receptor (EGFR), and adding MET and RET because published data indicate they are biomarkers of myxoid liposarcomas (MLS) [4, 5, 7]; we have found activated RON in our arrays [25], and there is a difference in the efficacy of the antibodies used in the arrays and those used for Western blotting [21]
The results showed that PDGFRB, RET, and MET were expressed and phosphorylated in all of the analyzed cases, whereas, expressed in all cases, EGFR was phosphorylated to different extents
Summary
The aim of this study was to analyze receptor tyrosine kinases (RTK) and their downstream signaling activation profile in myxoid liposarcomas (MLS) by investigating 14 molecularly profiled tumors: 7 naive and 7 treated with conventional chemotherapy/radiotherapy or the new drug trabectedin
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