[80] Transforming Growth Factor-ß and Connective Tissue Growth Factor Are Mitogenic Output Mediators of Wnt/ß-Catenin Signalling in Deep Fibromatosis

Sumi Varghese, William Kraybill, Joel Mayerson, Thomas Scharschmidt, Hans Iwenofu. OSUMC, Columbus

Background: Deep fibromatosis (includes mesenteric, abdominal and extraabdominal fibromatosis) are clonal proliferations of fibroblastic and myofibroblastic cells that are locally aggressive with high recurrence rates and no metastatic potential. Implicated molecular aberrations occur within the Wnt/beta-catenin pathway (APC and ß-catenin gene mutations). Transforming Growth Factor-beta (TFG- ß) and Connective Tissue Growth Factors (CTGF) are profibrotic growth factors, down stream from nuclear translocation of ß-catenin, that lead to increased fibrogenesis. CTGF (a downstream effector of TFG-ß) is a matricellular protein that modulates the activity of growth factors, adhesion molecules, integrins and extracellular matrix (ECM) thus playing a central role in tissue remodelling and fibrosis. It is plausible that given this role that CTGF might represent an important mediator in the pathogenesis of deep fibromatosis (DF). Recently there has been growing interest in use of ECM inhibitors for treatment of various fibrogenic diseases. Monoclonal antibodies targeting this are currently in clinical trials. Herein, a cohort of DF is evaluated for expression of ß-catenin, TGF-ß and CTGF using immunohistochemistry.
Design: 15 cases of DF were immunostained with TGF-ß, CTGF and ß-catenin biomarkers. Control group with 10 cases of normal skin and adjacent scar tissue were simultaneously immunostained with above mentioned markers. Using semiquantitative evaluation, any intensity of staining in >5% of the area of interest was considered positive (nuclear staining for ß-catenin, cytoplasmic staining for TGF-ß and CTGF).
Results: 15 of 15 DTs were positive for ß-catenin stain which was negative in control normal skin and scar. TGF-ß and CTGF were negative in 9 of 10 normal skin controls. TGF-ß were positive in 9 of 10 scar tissues and CTGF was positive in all cases of scar tissue. All 15 cases of DTs were positive for TGF-ß and CTGF There did not appear to be a difference in CTGF expression between DF and scar.

Table 1: Positive staining with biomarkers (in%)

	TGF-ß	CTGF	ß-catenin
Normal skin (n=10)	10	10	0
Scar tissue (n=10)	90	100	0
DF (n=15)	100	100	100

Conclusions: All cases of DF showed ß-catenin expression (suggesting Wnt/ ß-catenin pathway dysregulation) and high constitutive expression of downstream effectors; TGF-ß & CTGF. Myofibroblastic cells of scar tissue showed high expression of TGF-ß & CTGF but no expression of ß-catenin indicating different mechanisms. Constitutive expression of CTGF in DF has potential for enabling targeted therapy.
Category: Bone & Soft Tissue

Monday, March 19, 2012 1:00 PM

Poster Session II # 28, Monday Afternoon