Analysis of Wnt/Beta catenin signalling in desmoid tumors.
Desmoid tumors are fibromatous lesions occurring both sporadically and in patients with familial adenomatous polyposis (FAP). Because of the association of these tumors with the hereditary colorectal cancer syndrome FAP we set out to define the molecular events driving desmoid tumorigenesis, hypothezising these might be identical to events driving colorectal tumorigenesis. We found that whereas FAP-associated desmoid tumors are caused by germline APC mutations followed by somatic inactivation of the wild-type APC allele, sporadic desmoids are usually characterized by oncogenic mutations in the b-catenin gene, both identical molecular alterations to those found in the vast majority of colorectal cancers. Next we set out to investigate the cellular pathways activated by these mutations, and identified activation of the Wnt signaling pathway in desmoid tumors. Wnt signaling modulates expression of developmental genes and cell fate via beta-catenin, and has been implicated in many cancer types. Currently we are investigating tissue-specific downstream effectors of the Wnt pathway that might be responsible for the behaviour of these invasive fibrous tumors. Our findings also point to a role for this pathway in the regulation of normal myofibroblast proliferation and suggest novel treatments in desmoid tumors and other fibrous proliferative disorders.
Tejpar
S
S
Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven.
Michils
G
G
Denys
H
H
Van Dam
K
K
Nik
S A
SA
Jadidizadeh
A
A
Cassiman
J J
JJ
D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D018222:Desmoid Tumors / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin