Milea Timbergen

41 The growth factor regulatory signalling pathways in desmoid- type fibromatosis The growth regulatory signalling pathways The superfamily of transforming growth factor-ß (TGF-ß) regulates cell proliferation, differentiation, apoptosis and development. Two ligand subfamilies are recognized; the TGF-β nodal subfamily, and bone morphogenetic protein (BMP) subfamily. Ligand binding of either TGF-β ligands or BMP ligands facilitates the oligomerisation of type I and type II serine/threonine receptor kinases. In case of signalling, intracellular effectors, R-SMAD’s, are phosphorylated in the cytoplasm whereupon they partner with SMAD4 and translocate to the nucleus. In the nucleus they regulate, in conjunction with transcription factors/corepressors or co-activators, the transcription of TGF-ß target genes. Growth factor signalling pathways are initiated by various growth factors (e.g., insulin-like growth factors, platelet-derived growth factor, and hepatocyte growth factor) and induce phosphorylation of downstream targets via activation of their associated receptor tyrosine kinases. The signal is transduced through various intracellular intermediate molecules, frequently including PI3 kinase/AKT and Ras/Raf/MAPK pathways to ultimately affect gene expression (reviewed by Massague et al. 135 ). The growth factor regulatory signalling pathways and their role and therapeutic potential in desmoid-type fibromatosis The role of TGF-ß in DTF has been established by the expression of TGF-ß target genes (e.g., several collagen types and metalloproteinases) and by the upregulation of TGF-ß signalling pathway components (phospho-SMAD2 and phospho-SMAD3, ɑ-SMA and PAI1) in comparison to normal fascia 66 . Mignemi et al. investigated TGF-ß signalling comparing DTF tissue with hypertrophic scars and fibrous tissue in human samples. It was discovered that the levels of TGF-ß receptor type 1 were similar in DTF and scar tissue, but that this receptor could not be detected in fibrous tissue. Phosphorylated SMAD2/3 could be detected in the majority of DTF samples (74%) but only in a minority of scar tissues (29%) and not at all in fibrous tissue 136 . Additionally, TGF-ß stimulates β-catenin transcriptional activity, which indicates that this growth factor might play an important role in the development of DTF 66 . Multiple studies reported overexpression of platelet derived growth factors and their associated receptors (PDGFɑ, PDGFRɑ, PDGFß and PDGFRß) in neoplastic fibrous proliferations including DTF and myofibromatoses 137, 138 . 2