c-myc overexpression causes anaplasia in medulloblastoma.
Both anaplasia and increased c-myc gene expression have been shown to be negative prognostic indicators for survival in medulloblastoma patients. myc gene amplification has been identified in many large cell/anaplastic medulloblastoma, but no causative link between c-myc and anaplastic changes has been established. To address this, we stably overexpressed c-myc in two medulloblastoma cell lines, DAOY and UW228, and examined the changes in growth characteristics. When analyzed in vitro, cell lines with increased levels of c-myc had higher rates of growth and apoptosis as well as significantly improved ability to form colonies in soft agar compared with control. When injected s.c. into nu/nu mice, flank xenograft tumors with high levels of c-myc in DAOY cell line background were 75% larger than those derived from control. Overexpression of c-myc was required for tumor formation by UW228 cells. Most remarkably, the histopathology of the Myc tumors was severely anaplastic, with large areas of necrosis/apoptosis, increased nuclear size, and macronucleoli. Indices of proliferation and apoptosis were also significantly higher in Myc xenografts. Thus, c-myc seems to play a causal role in inducing anaplasia in medulloblastoma. Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms.
Stearns
Duncan
D
Department of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA. steardu@jhmi.edu
Chaudhry
Aneeka
A
Abel
Ty W
TW
Burger
Peter C
PC
Dang
Chi V
CV
Eberhart
Charles G
CG
D000708:Anaplasia; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009336:Necrosis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc