Molecular Pathogenesis of Desmoid Tumors

Abstract

Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors in which beta-catenin/TCF3 mediated Wnt signaling is activated. More than 80% of desmoid tumors contain activating mutations in ß-Catenin which leads to up-regulation of ß-Catenin. The functional consequences of up-regulation of ß-Catenin as an oncogene are complex in different tumors and tissues. TOP/FOP constructs are using to identify the activation of ß-Catenin-TCF4-mediated transcription. We have already shown constitutive ß-Catenin /TCF transcriptional activity in desmoids tumors. cDNA microarray analysis showed that differentially expressed genes in desmoid tumors were different than known Wnt target genes in colorectal cancer. (except for MMP7). Also we have shown that IGFBP6 is a direct target of ß-Catenin -TCF4-mediated repression in desmoid. Different ß-Catenin mutant can increase significantly TOP/FOP ratio in HEK293T cell line 32-52 folds while they cannot significantly modulate TOP/FOP ratio in CHO cell line. On the other hand, IGFBP6 as a direct target of ß-Catenin -TCF4-mediated transcription is down-regulated by S33 mutant ß-Catenin but not responsive to other mutant or deleted forms of ß-Catenin in CHO cell line. In Hek293T cell line, this promoter is slightly activated but no significant change. Here we show that induction of constitutive ß-Catenin /TCF transcriptional activity is dependent to cell context and TGF-Beta signaling pathway may regulate it in desmoid tumors. Our preliminary results suggest an additional role for TGF-Beta signaling pathway in modulating downstream targets in desmoids. TGF-Beta is activated in desmoid and their phenotype resembles mostly that of TGF-Beta activated myofibroblasts. In conclusion, we show that activation of constitutive ß-Catenin /TCF transcriptional activity depends to cell context and different mutant form of ß-Catenin can play different role in modulation of target genes. TGF-Beta signaling pathway may be the main regulator in this response in our tumor samples.