c-Myc and beta-catenin cooperate with loss of p53 to generate multiple members of the primitive neuroectodermal tumor family in mice.
Primitive neuroectodermal tumors (PNETs) are a family of primary malignant brain tumors that include medulloblastomas. Although genetic models of a subset of medulloblastomas are documented over the past decade, the molecular basis of other subclasses of PNET remains unclear. As elevated c-Myc expression, activation of Wnt/beta-catenin signaling and dysfunction of p53 are seen in human PNETs, we investigated what role these abnormalities have in the formation of PNETs. Incorporating these abnormalities, we generated supratentorial PNET (sPNET) in mice using somatic cell gene transfer. We show that sPNETs arise from GFAP-expressing cells by forced c-Myc expression combined with p53 inactivation. beta-catenin activation promotes tumor progression and induces divergent differentiation. These c-Myc+beta-catenin-induced PNETs are histologically similar to large cell/anaplastic medulloblastomas and can occur in both cerebrum and cerebellum. Furthermore, we have obtained one PNET with marked epithelial differentiation having histological resemblance to choroid plexus carcinoma in this series. Our results in mice suggest that sPNET with varied differentiation and large cell/anaplastic medulloblastomas may be two tumor groups with similar genetic foundations. These data provide insights into the biology and classification of human PNETs and suggest that multiple tumor types or variants can be generated from a fixed set of genetic abnormalities.
Momota
H
H
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Shih
A H
AH
Edgar
M A
MA
Holland
E C
EC
D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D016259:Genes, myc; D008527:Medulloblastoma / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018242:Neuroectodermal Tumors, Primitive / Q000145:classification / Q000209:etiology* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction; D015173:Supratentorial Neoplasms / Q000209:etiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin