Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Hedgehog (HH) pathway regulates fundamental processes in embryonic development, including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. In the vertebrate pathway, Sonic hedgehog (SHH) binds to Patched1 (PTCH1), which relieves its inhibition of Smoothened (SMO), allowing the GLI family of transcription factors to translocate to the nucleus and activate HH target genes such as GLI1, GLI2, PTCH1, CYCLIN D1, BCL-2, and MYCN. The HH pathway is also an active participant in tumorigenesis. In 1996, loss-of-function mutation in PTCH1 was discovered to be the cause of nevoid basal cell carcinoma syndrome (NBCCS, or Gorlin syndrome), an autosomal dominant disease associated with increased rates of basal cell carcinoma (BCC), medulloblastoma (MB), and rarely, rhabdomyosarcoma. It is now estimated that 100% of sporadic BCC and up to 20% to 30% of MB also harbor activating HH pathway mutations. Together, these discoveries firmly established the linkage between HH pathway activation and cancer development. Intense research has since been focused on further defining the role of the HH pathway in BCC and MB and potential therapeutic strategies to inhibit HH signaling. Early clinical trials of SMO inhibitors have shown promising results in the treatment of adult BCC and SHH-driven MB. More recently, a number of other pediatric cancers have been reported to show HH activity, making these tumors potential candidates for HH inhibitor therapy. To date however, no HH pathway mutations have been identified in other pediatric cancers. This review will describe the HH pathway signaling in development and cancer with a focus on recent evidence for HH pathway activation in central nervous system (CNS) and non-CNS pediatric cancers.
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PMID:Hedgehog Pathway in Pediatric Cancers: They're Not Just for Brain Tumors Anymore. 2445 4

The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAX-FOXO1s. Our data demonstrate that PAX-FOXO1s, but not wild-type PAX3 or PAX7, trigger the trans-differentiation of neural cells into FP-RMS-like cells with myogenic characteristics. In parallel, PAX-FOXO1s remodel the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, expression of PAX-FOXO1s, similar to wild-type PAX3/7, reduce the levels of CDK-CYCLIN activity and increase the fraction of cells in G1. Introduction of CYCLIN D1 or MYCN overcomes this PAX-FOXO1-mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism that can explain the apparent limited oncogenicity of PAX-FOXO1 fusion transcription factors. They are also consistent with certain clinical reports indicative of a neural origin of FP-RMS.
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PMID:The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition. 3317 61