Functional mapping of receptor tyrosine kinases in myxoid liposarcoma.
OBJECTIVE
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.


METHODS
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)/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.


CONCLUSIONS
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.
Negri
Tiziana
T
Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Virdis
Emanuela
E
Brich
Silvia
S
Bozzi
Fabio
F
Tamborini
Elena
E
Tarantino
Eva
E
Jocollè
Genny
G
Cassinelli
Giuliana
G
Grosso
Federica
F
Sanfilippo
Roberta
R
Casalini
Patrizia
P
Greco
Angela
A
Pierotti
Marco A
MA
Pilotti
Silvana
S
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D004149:Dioxoles / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D018208:Liposarcoma, Myxoid / Q000201:enzymology* / Q000378:metabolism / Q000628:therapy; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use; D000077606:Trabectedin
D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D020794:Receptor Protein-Tyrosine Kinases; D000077606:Trabectedin