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 b...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2006-01, Vol.66 (2), p.673-681
Main Authors: STEARNS, Duncan, CHAUDHRY, Aneeka, ABEL, Ty W, BURGER, Peter C, DANG, Chi V, EBERHART, Charles G
Format: Article
Language:English
Subjects:
Anaplasia
Animals
Apoptosis
Biological and medical sciences
Cell Proliferation
Cerebellar Neoplasms - genetics
Cerebellar Neoplasms - pathology
Humans
Medical sciences
Medulloblastoma - genetics
Medulloblastoma - pathology
Mice
Necrosis
Neurology
Proto-Oncogene Proteins c-myc - biosynthesis
Proto-Oncogene Proteins c-myc - physiology
Transplantation, Heterologous
Tumor Cells, Cultured
Tumors of the nervous system. Phacomatoses
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-1580