Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis.
OBJECTIVE
To explore the molecular bases of potential new pharmacologic targets in aggressive fibromatosis (desmoid tumor).


METHODS
Tumor specimens from 14 patients surgically treated for aggressive fibromatosis (6 familial adenomatous polyposis and 8 sporadic cases), analyzed for adenomatous polyposis coli (APC) and CTNNB1 (beta-catenin) mutations, were further investigated for beta-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor alpha (PDGFRA)/PDGF receptor beta (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach.


RESULTS
No CTNNB1 (beta-catenin) mutations were found in the familial adenomatous polyposis patients, but previously reported activating mutations were found in six of the eight sporadic patients. All of the cases carrying an altered WNT pathway showed nuclear and cytoplasmic immunoreactivity for beta-catenin, whereas beta-catenin expression was restricted to the cytoplasm in the sporadic patients lacking CTNNB1 mutations. COX-2 protein and mRNA overexpression was detected in all 14 cases, together with the expression and phosphorylation of PDGFRA and PDGFRB, which in turn paralleled the presence of their cognate ligands. No PDGFRB mutations were found. The results are consistent with PDGFRA and PDGFRB activation sustained by an autocrine/paracrine loop.


CONCLUSIONS
Aggressive fibromatosis is characterized by WNT/oncogene pathway alterations triggering COX-2-mediated constitutive coactivation of PDGFRA and PDGFRB, and may therefore benefit from combined nonsteroidal anti-inflammatory drug + tyrosine kinase inhibitor treatment.
Signoroni
Stefano
S
Experimental Molecular Pathology, Department of Pathology, Fondazione IRCSS Istituto Nazionale dei Tumori, Milan, Italy.
Frattini
Milo
M
Negri
Tiziana
T
Pastore
Elisa
E
Tamborini
Elena
E
Casieri
Paola
P
Orsenigo
Marta
M
Da Riva
Luca
L
Radice
Paolo
P
Sala
Paola
P
Gronchi
Alessandro
A
Bertario
Lucio
L
Pierotti
Marco A
MA
Pilotti
Silvana
S
D000293:Adolescent; D000328:Adult; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D005260:Female; D018222:Desmoid Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D051176:beta Catenin / Q000235:genetics