Evasion of cell senescence in SHH medulloblastoma
| Autor: | Frédéric Charron, Shannon M. Swikert, Lukas Tamayo-Orrego |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Senescence Genome instability preneoplasia medicine.disease_cause Loss of heterozygosity sonic hedgehog 03 medical and health sciences Ptch1 medicine Animals Humans Hedgehog Proteins TP53 Sonic hedgehog neoplasms Molecular Biology Cellular Senescence Genetics Medulloblastoma Extra Views biology p53 Cell Biology medicine.disease Hedgehog signaling pathway nervous system diseases stomatognathic diseases 030104 developmental biology PTCH1 cell senescence Mutation Cancer research biology.protein Tumor Suppressor Protein p53 Carcinogenesis Signal Transduction Developmental Biology |
| Zdroj: | Cell Cycle |
| ISSN: | 1551-4005 1538-4101 |
| DOI: | 10.1080/15384101.2016.1189044 |
| Popis: | The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1+/− mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis. |
| Databáze: | OpenAIRE |
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