Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis

Stefano Signoroni, Milo Frattini, Tiziana Negri, Elisa Pastore, Elena Tamborini, Paola Casieri, Marta Orsenigo, Luca Da Riva, Paolo Radice, Paola Sala, Alessandro Gronchi, Lucio Bertario, Marco A. Pierotti, Silvana Pilotti

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Abstract

Purpose: To explore the molecular bases of potential new pharmacologic targets in aggressive fibromatosis (desmoid tumor). Experimental Design: 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 (β-catenin) mutations, were further investigated for β-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor α (PDGFRA)/PDGF receptor β (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach. Results: No CTNNB1 (β-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 β-catenin, whereas β-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.

Original languageEnglish
Pages (from-to)5034-5040
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number17
DOIs
Publication statusPublished - Sep 1 2007

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Signoroni, S., Frattini, M., Negri, T., Pastore, E., Tamborini, E., Casieri, P., Orsenigo, M., Da Riva, L., Radice, P., Sala, P., Gronchi, A., Bertario, L., Pierotti, M. A., & Pilotti, S. (2007). Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis. Clinical Cancer Research, 13(17), 5034-5040. https://doi.org/10.1158/1078-0432.CCR-07-0336