Ret Activation in Medullary Carcinomas

Pierotti, Marco A.; Arighi, Elena; Degl’Innocenti, Debora; Borrello, Maria Grazia

doi:10.1007/1-4020-8107-3_23

Cited by 2 publications

(1 citation statement)

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“…The presence of glycosaminoglycans (of which the stroma of usual type MLS is rich) favoring the concentration of GDNF in the vicinity of GFRα1 and/or RET/GFRα1 complexes may contribute to RET activation (8). RET activating mutations and amplifications have also been rarely described (9,10).…”

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Functional Mapping of Receptor Tyrosine Kinases in Myxoid Liposarcoma

Negri

Virdis

Brich

et al. 2010

Clinical Cancer Research

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Purpose: 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.Experimental Design: 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.Results: 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)/GFRα3 (glial cell-derived neurotrophic factor family receptor α3)/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 GFRα3 (RET coreceptor)/arteminmediated 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.Conclusions: These findings highlight the particular cell-specific activation profile of RET/GFRα3 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 GFRα3.

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