title: Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis.
abstract: 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.
authors.affiliation: Experimental Molecular Pathology, Department of Pathology, Fondazione IRCSS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Signoroni
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Negri
authors.forename: Elisa
authors.initials: E
authors.lastname: Pastore
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
authors.forename: Paola
authors.initials: P
authors.lastname: Casieri
authors.forename: Marta
authors.initials: M
authors.lastname: Orsenigo
authors.forename: Luca
authors.initials: L
authors.lastname: Da Riva
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Paola
authors.initials: P
authors.lastname: Sala
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.forename: Lucio
authors.initials: L
authors.lastname: Bertario
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
mesh_terms: 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