Milea Timbergen

33 enhancing their stability and promoting internalization when bound to Patched (PTCH1). Binding of Hh proteins to the canonical receptor PTCH1 and to co-receptors GAS1, BOC and CDON initiates Hh signalling. This results in the release of PTCH1 mediated repression of the transmembrane protein Smoothened (SMO), a G-protein coupled receptor (GPCR)-like protein, which consequently leads to an accumulation of SMO in the cilia and phosphorylation of its cytoplasmic tail. Smoothened, regulates the downstream signal transduction which dissociates glioma associated oncogene (GLI) proteins, from kinesin- family protein, KIF7 and SUFU. GLI proteins serve as bifunctional transcription factors, capable of activating and repressing transcription, and form a key intracellular component of the Hh pathway (reviewed by Wu et al. 92 and Briscoe and Thérond 93 ). The Hedgehog signalling pathway in cancer Aberrant Hh signalling in cancer is attributed to an increased endogenous Hh ligand expression, or to activating mutations of Hh pathway components (reviewed by Wu et al. 92 ). Aberrant uncontrolled activation of Hh has been described in numerous tumour types including: rhabdomyosarcoma 94 , colorectal cancer 95 , basal cell carcinoma 96 and medulloblastoma 97 . The Hedgehog signalling pathway and its role and therapeutic potential in des- moid-type fibromatosis As the Hh pathway has the ability to maintain mesenchymal progenitor cells in a less differentiated state with greater proliferative capacity, it is possible that it influences proliferation of DTF cells in a similar manner because of the mesenchymal origin of these cells 61 . Ghanbari et al. showed that Hh signalling is active in DTF by identifying a significant upregulation of Hh target genes GLI1 , PTCH1 and Hedgehog interacting protein (HHIP) in human DTF samples compared to adjacent normal tissues. Additionally it was demonstrated that expression of Gli1 , Gli2 , and Ptch1 in mouse ( Apc +/1638N ) tumours was upregulated compared to normal tissue. In vivo , pharmacological inhibition of Hh with triparanol, which works by interference with the posttranslational modification of Hh signalling molecules and with the sterol-sensing domain of the receptor PTCH1, led to a reduction in tumour volume in Apc +/1638N mice. Genetic approaches to reduce Hh signalling in DTF using Apc +/ 1638N ; Gli2 +/− mouse models, gave rise to the development of fewer and smaller tumours (Table 1) 61, 98 . Current inhibition of the Hh signalling pathway in the clinic acts via the pharmacological inhibition of SMO, however no clinical trials studying Hh inhibitors in DTF have been carried out. Figure 2 displays the Hh pathway and proposed working mechanism of target drugs in DTF. 2