Growth rate and myofibroblast differentiation of desmoid fibroblast-like cells are modulated by TGF-β signaling

Abstract Desmoid-like fibromatosis (DF) is a rare myofibroblastic benign tumor, often associated with local and repeated injuries, spontaneous regression and stabilization of disease progression suggesting the involvement of altered Wnt/-catenin signaling activation and/or aberrant response of the DF cells to external environmental stimuli. The aim of this study was to investigate the response of DF cells to microenvironmental factors such as inflammatory and growth factors or hormones. We observed that the inflammatory cytokine, transforming growth factor- (TGF-1) stimulated cell growth and myofibroblast differentiation of DF cells regardless of the presence of a -catenin mutation. The role of TGF-1 in cell growth and myogenic differentiation of in vitro cultures of primary DF cells and normal fibroblasts was investigated by gene and protein expression analyses. We demonstrated that TGF-1 exerted its role via the canonical Smad pathway with the phosphorylation of Smad3 being crucial for TGF-1 dependent DF cell growth and myofibroblastic differentiation. Furthermore we demonstrated that cell confluence is a critical determinant of TGF-1 inducing the DF myofibroblast differentiation, implying that the intercellular communications have an important role on the DF myofibroblast behavior. We observed the formation of an increased stress-fiber pattern in DF cells with increased projected cell area and stronger cell-cell contacts in presence of TGF-1. These results demonstrated that TGF-1 plays a crucial role in the DF cells growth and, together with cell-cell interactions, in DF myofibroblast conversion; we also highlighted that the cellular sensitivity to this cytokine was an intrinsic feature of the DF cells.