4546

Desmoid tumors (DT) are rare, locally invasive lesions of fibroblastic origin that occur spontaneously or in association with familial adenomatous polyposis (FAP). DT of either presentation often possess somatic mutations within the adenomatous polyposis coli (APC) or B-catenin gene, resulting in B-catenin stabilization and activation of the Wnt signaling pathway. Previous studies have implicated over-expression of B-catenin in the development of desmoid tumors; however, the specific molecular pathways for desmoid proliferation have yet to be elucidated. We are currently examining the role of the tyrosine kinases c-src and c-kit as potential targets for drug therapy in patients with desmoid tumors. To investigate activation of B-catenin signaling by tyrosine kinases, protein lysates were prepared from intra-abdominal desmoid tumors and normal fascia of FAP patients for immunoprecipitation and Western analysis. We found increased levels of B-catenin in desmoid tumors relative to normal tissue, consistent with B-catenin over-expression in similar cancers. We also showed increased levels of c-src and c-kit in desmoids compared with normal tissue. However, B-catenin tyrosine phosphorylation among tumors was decreased when compared with normal tissue, despite the increased amount of B-catenin and tyrosine kinases present in tumors. Furthermore, levels of activated c-src were not increased in tumors relative to normal tissue, although we did find increased levels of activated c-kit. Taken together, these results suggest a role for B-catenin as a transcriptional activator of desmoid proliferation, rather than a dysfunctional regulator of cell-cell adhesion as seen in other human cancers. Future experiments will be conducted to investigate the role of tyrosine kinases in desmoid tumors using in-vitro inhibitor assays. Further insight into desmoid biology, including the pivotal role of the B-catenin/Wnt pathway, will help target novel drug regimens to limit the morbidity and mortality associated with this disease.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]