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.

Pazopanib or methotrexate–vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): a non-comparative, randomised, open-label, multicentre, phase 2 study

“…30 THBS4 is an important pro-angiogenic factor that contributes to tumor growth via TGF-β pathway activation, which mediates Wnt/β-Catenin signaling in DT. 31,32 This study has limitations. It was a non-comparative randomized trial, therefore precluding direct comparison of the chemotherapy regimen with pazopanib.…”

Molecular Pathogenesis of Sporadic Desmoid Tumours and Its Implications for Novel Therapies: A Systematised Narrative Review

“…β-Catenin primarily coordinates cell proliferation, differentiation and fate, with its deregulated signalling being intrinsically linked to the development of several human cancers, such as skin, colon and breast cancer [ 13 , 14 ]. β-Catenin demonstrated aberrant nuclear immunoreactivity in at least 47% of DTF cases [ 24 – 33 ]. DTF cases with a mutated CTNNB1 gene also demonstrated more frequent β-catenin nuclear expression (39/43, 90.7%) compared with cases with wild-type CTNNB1 (Fisher’s exact test, 17/27, 63.0%, p = 0.012) [ 28 ].…”

“…Two studies examined TFGβ signalling. Varghese et al illustrated moderate-strong TGFβ and connective tissue growth factor (CTGF) immunoreactivity in 100% and 66.7% of DTF cases, respectively [ 33 ]. Mignemi et al demonstrated phosphorylated SMAD2/3 immunoreactivity in 96% of their DTF cohort, which was significantly greater than both hypertrophic scar and normal fibrous tissue (Kruskal–Wallis test, p < 0.0001; Dunn’s post-hoc test, p < 0.001) [ 32 ].…”

“…The role of aberrant Wnt/β-catenin signalling in desmoid pathogenesis is well established [ 15 – 18 ]. Accordingly, this review found aberrant β-catenin expression in almost half of DTF cases within each study [ 24 – 33 ]. Mutated β-catenin also enhanced its pathologic role compared with its wild-type counterpart, producing greater overexpression of downstream target genes such as cyclin D1 [ 26 , 27 , 29 , 31 ].…”

Antihypertensive and Antifibrosis Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms

“…myofibroblasts to encode fibrillary collagen (Dobaczewski et al, 2011) and participate in the transition from stable hypertrophy to heart failure (Lim and Zhu, 2006). Meanwhile, it was also found that CTGF, as a downstream mediator of TGFβ 1, also has a great effect on fibroblasts induced by TGFβ 1 (Varghese et al, 2017) and significantly upregulated in human heart failure and the myocardial fibrosis-associated animal model (Koshman et al, 2013). In addition, TNF-α, as a proinflammatory cytokine, promotes collagen deposition in fibrotic myocardium myocardia and ECM accumulation by affecting MMP expression and activity, which can lead to myocardial fibrosis (Leask, 2015).…”