Milea Timbergen

37 The JAK/ STAT signalling pathway in desmoid-type fibromatosis The JAK/STAT signalling pathway The Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) signalling pathway regulates cell proliferation, survival, differentiation, migration and apoptosis, and has a role in pathogen resistance. The JAK/STAT pathway is the main signalling mechanism for many cytokines and growth factors. A variety of ligands e.g., interferon-ɑ /interferon-ß (IFN), secreted by leukocytes (IFN-ɑ), fibroblasts (IFN-ß) and various other cells involved in immune responses, and interleukins (IL) together with their cognate receptors, stimulate the pathway. Ligand binding causes receptor dimerisation and subsequent activation of the JAK tyrosine kinases associated with the cytoplasmic domains of the receptor. JAKs in close proximity are trans-phosphorylated and phosphorylate the receptors. The phosphorylated receptor sites can then serve as docking sites for cytoplasmic transcriptions factors (STATs). These STATs become phosphorylated by JAKs, dimerise and are translocated into the nucleus where they activate or repress the transcription of target genes (reviewed by O’Shea et al. 110 ). The JAK/STAT signalling pathway in cancer Dysregulation of the JAK/STAT signalling pathway has been observed in several cancers including haematological and solid malignancies such as breast (reviewed by Banerjee and Resat 111 ) and prostate cancer (reviewed by Bishop et al. 112 ). Hallmarks of JAK/STAT dysregulation are aberrant cytokine production, the occurrence of activating JAK mutations or mutations in other upstream oncogenes and activating mutations in STAT (reviewed by O’Shea et al. 110 ). The JAK/STAT signalling pathway and its role and therapeutic potential in des- moid-type fibromatosis In both human DTF samples and murine DTF models ( Apc/Apc 1638N ), an increased expression of type 1 IFN response genes (e.g., MxA, MxB, IFITI1, and IFNAR1 ) have been identified suggesting an activated JAK/STAT signalling. Genes activated by this signalling pathway, have been shown to have an anti-proliferative effect on DTF cells and normal fibroblasts (Table 1) 63 . Regression of DTF after treatment with IFN has been described in several case reports 113-116 . A retrospective study by Leithner et al. examined thirteen DTF patients receiving IFN-ɑ ± tretinoin (a natural metabolite of vitamin A [retinol]). This study indicated no evidence of disease in seven out of nine patients (adjuvant group) and a mean disease-free interval of 22 months (±18 months), and progressive disease in two patients. 2