The SIGnaling Network
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Pathway ID: SIGNOR-RMSView in NDEx

Description: Rhabdomyosarcoma (RMS) is a relatively rare cancer but is the most common form of soft-tissue sarcomas in young adults children and children. RMS can originate as a consequence of myogenic precursors failing to differentiate into normal muscle and is characterised by two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ERMS is the most common form of the disease, comprises about 60% of cases, and has a more favourable outcome than ARMS. It’s characterized by a wide range of genetic aberrations and the most frequent is the loss of heterozygosity at the 11p15 locus, a region that encodes insulin-like growth factor 2 (IGF2). ARMS is the most aggressive form of RMS with a poorer prognosis and more prone to metastasis. It’s characterized by genetic translocations that result in chimeric protein that fuse the DNA binding domain of the paired box proteins 3 or 7 (PAX3 or PAX7) to the transactivation domain of a forkhead transcription factor (FOXO1). RMS display many defects in growth-factor signalling pathways and cell-cycle checkpoints that lead to cell growth and proliferation. The most frequently affected pathways are fibroblast growth factor (FGF), insulin-like growth factor (IGF), hepatocyte growth factor, and platelet-derived growth factor. PAX-FOXO1 proteins can activate these pathways by transcriptional activation of IGFR1, FGFR4, MET (c-Met) and PDGFRA genes. In 93% of RMS cases there is an alteration of the receptor tyrosine kinase/RAS/ PI3K axis and that alterations appeared to hinge on the FGF and IGF pathways. FGF and IGF pathways converge on cell-cycle regulators such as the cell-cycle regulator p21 (CDKN1A), and the cell-cycle regulator p14 (CDKN2A). p21 is induced in myoblast differentiation and blocks cell-cycle progression ; is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these proteins in RMS contributes to the silencing of p21. p14 is tumour suppressor and copy number deletions in CDKN2A were found in 2% of the RMS cancers. TBX2, a T-box gene family member, is overexpressed in both ERMS and ARMS cells. it is regulated by PAX3 and was found to induce a downregulation of p14 and to be a direct repressor of p21 in RMS.

Curated by: Marta Iannuccelli