title: TGF-β and CTGF are Mitogenic Output Mediators of Wnt/β-Catenin Signaling in Desmoid Fibromatosis.
abstract: Desmoid fibromatosis is a locally aggressive clonal fibroblastic proliferation with high recurrence rates and no metastatic potential. Implicated molecular aberrations occur within the Wnt/β-catenin pathway (APC and β-catenin gene mutations). Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are profibrotic growth factors, downstream from nuclear translocation of β-catenin, that lead to increased fibrogenesis. CTGF (a downstream effector of TGF-β) is a matricellular protein that modulates the activity of growth factors, adhesion molecules, integrins, and extracellular matrix thus playing a central role in tissue remodeling and fibrosis. Recently there has been growing interest in use of extracellular matrix inhibitors for treatment of various fibrogenic diseases. Desmoid fibromatosis samples (n=15) were evaluated for expression of β-catenin, TGF-β, and CTGF using immunohistochemistry on formalin paraffin-embedded material. A control group comprising scar tissue and adjacent normal skin (n=10) were simultaneously immunostained with above mentioned markers. Real-time polymerase chain reaction was performed on frozen specimens of desmoid fibromatosis (n=6) and normal skin (n=2). All 15 desmoid tumors were positive for β-catenin (surrogate marker of Wnt/β-catenin pathway dysregulation) which was negative in control normal skin and scar samples. TGF-β and CTGF were negative in 9 of 10 normal skin controls. TGF-β and CTGF were positive in all cases of scar tissue. All 15 cases of desmoid tumors were positive for TGF-β and CTGF. The real-time polymerase chain reaction showed higher expression levels of TGF-β and CTGF in desmoid fibromatosis compared with normal skin. The high constitutive expression of β-catenin downstream effectors; TGF-β, CTGF has the potential for enabling targeted therapy.
authors.affiliation: *Department of Pathology and Laboratory Medicine †Comprehensive Cancer Center ‡Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH §Department of Surgery, Division of Surgical Oncology ∥Department of Orthopedics, The Ohio State University Medical Center.
authors.forename: Sumi
authors.initials: S
authors.lastname: Varghese
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Braggio
authors.forename: Jessica
authors.initials: J
authors.lastname: Gillespie
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Toland
authors.forename: Raphael
authors.initials: R
authors.lastname: Pollock
authors.forename: Joel
authors.initials: J
authors.lastname: Mayerson
authors.forename: Thomas
authors.initials: T
authors.lastname: Scharschmidt
authors.forename: Obiajulu H
authors.initials: OH
authors.lastname: Iwenofu
mesh_terms: D000328:Adult; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D005260:Female; D018222:Desmoid Tumors / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D008934:Mitogens; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; D055513:Connective Tissue Growth Factor