Milea Timbergen

24 isolated limb perfusion 21 . Although not widely used, as the evidence for their effect in DTF is only based on small patient series, some patients benefit from these local therapies for example when limb salvage is the treatment goal 22-25 . Besides targeted drugs, other systemic options include more classic chemotherapeutic compounds like vinblastine, vinorelbine, methotrexate, doxorubicin, dacarbazin, either as a single agent or as combination therapy 21 . Although most studies describe small retrospective case series and include patients who received other treatments prior to their cytotoxic treatment, multiple studies indicate a potential effect of these drug regimens 26-29 . The aggressive growth behaviour, in combination with the high recurrence rate, creates the need for effective drugs targeting the molecular mechanisms that drive tumorigenesis 30, 31 . This is especially true for large, symptomatic tumours, which cannot be treated surgically, or with radiotherapy. As stated above, several systemic options are available with variable efficacy in different patients, but no consensus about the nature and the sequence of systemic treatments has been established 21 . As of yet, the exact working mechanisms of these systemic agents in DTF remain unclear. A better understanding of the molecular mechanisms that prompt tumorigenesis and influence DTF progression will contribute to the development and implementation of new targeted therapies. This review comprehensively screened the available literature regarding active cell signalling and biochemical pathways and reviews pathway-specific targeted drugs investigated in DTF. Additionally, the challenges of DTF research, as well as the future perspectives, are discussed. The abbreviations used in the text, tables and figures are explained in Supplemental Material 1. The Wnt/ß-catenin signalling pathway in desmoid-type fibromatosis The Wnt/ß-catenin signalling pathway The canonical Wnt/ß-catenin pathway coordinates cell fate decisions during the developmental process and in adult homeostasis. Target genes of this signalling pathway are involved in regulating the balance between self-renewal, differentiation, apoptosis, and in stem cell maintenance (reviewed by Nusse and Clevers 32 and Steinhart and Angers 33 ). Activation of the Wnt/β-catenin pathway involves a Wnt ligand binding to the transmembrane receptor Frizzled, forming a complex with a co-receptor that is the LDL receptor-related protein 5 or 6 (LRP5 and LRP6). The ß-catenin protein is a key mediator in the Wnt/β- 2