Cyclooxygenase-two (COX-2) modulates proliferation in aggressive fibromatosis (desmoid tumor)

Raymond Poon, Ron Smits, Catherine Li, Shantie Jagmohan-Changur, Michael Kong, Sophia Cheon, Chunying Yu, Riccardo Fodde, Benjamin A. Alman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

92 Citations (Scopus)

Abstract

Aggressive fibromatosis is a locally invasive soft tissue lesion. Seventy-five per cent of cases harbor a somatic mutation in either the APC or β-catenin genes, resulting in β-catenin protein stabilization. Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin synthesis that modulates the formation of colonic neoplasia, especially in cases due to mutations resulting in β-catenin stabilization. Human aggressive fibromatoses and lesions from the Apc+/Apc1638N mouse (a routine model for Apc-driven fibromatosis) demonstrated elevated COX-2 levels. COX-2 blockade either by the selective agent DFU or by non-selective COX blocking agents results in reduced proliferation in human tumor cell cultures. Breeding mice with Cox-2-/- mice resulted in no difference in number of aggressive fibromatoses formed, but in a smaller tumor size, while there was a decrease in number of GI lesions by 50%. Mice fed various COX blocking agents also showed a decline in tumor size. COX-2 expression was regulated by tcf-dependent transcription in this lesion. COX-2 partially regulates proliferation due to β-catenin stabilization in aggressive fibromatosis. Although COX blockade alone does not cause tumor regression, this data suggests that it may have a role as an adjuvant therapy to slow tumor growth in this lesion.

Original languageEnglish
Pages (from-to)451-460
Number of pages10
JournalOncogene
Volume20
Issue number4
DOIs
Publication statusPublished - 25 Jan 2001

Bibliographical note

Funding Information:
Funded by grants from the National Cancer institute of Canada with funds from the Terry Fox Run, grant number 9129, to BA Alman; The Medical Research Council of Canada, grant number MT-15136, to BA Alman; and The Dutch Cancer Society (KWF), grant number RUL-98-1652, to R Smits and R Fodde. The DFU, MF Tricyclic and Sulindac formulated into mouse chow, the control mouse diet, and the DFU for use in cell cultures were all obtained from Merck Frosst, Quebec, Canada. The drug levels in the mice were tested at Merck Frosst, Quebec, Canada. The DN-tcf-4E was obtained from Osamu Tetsu and Frank McCormick, who produced this from a construct they obtained from Hans Clevers.

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