c-Myc is required for maintenance of glioma cancer stem cells.
Abstract
BACKGROUND: Malignant gliomas rank among the most lethal cancers. Gliomas display
a striking cellular heterogeneity with a hierarchy of differentiation states. Recent
studies support the existence of cancer stem cells in gliomas that are functionally
defined by their capacity for extensive self-renewal and formation of secondary tumors
that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles
in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem
cell biology as these cells share characteristics with normal stem cells. METHODOLOGY/PRINCIPAL
FINDINGS: Based on previous methods that we and others have employed, tumor cell populations
were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1).
We characterized c-Myc expression in matched tumor cell populations using real time
PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc
is highly expressed in glioma cancer stem cells relative to non-stem glioma cells.
To interrogate the significance of c-Myc expression in glioma cancer stem cells, we
targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown
of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle
arrest in the G(0)/G(1) phase and increased apoptosis. Non-stem glioma cells displayed
limited dependence on c-Myc expression for survival and proliferation. Further, glioma
cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro
or tumors when xenotransplanted into the brains of immunocompromised mice. CONCLUSIONS/SIGNIFICANCE:
These findings support a central role of c-Myc in regulating proliferation and survival
of glioma cancer stem cells. Targeting core stem cell pathways may offer improved
therapeutic approaches for advanced cancers.
Type
Journal articleSubject
AC133 AntigenAnimals
Antigens, CD
Brain Neoplasms
Cell Cycle
Cell Proliferation
Gene Expression Regulation, Neoplastic
Glioma
Glycoproteins
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Neoplasms
Neoplastic Stem Cells
Oncogene Proteins
Peptides
Proto-Oncogene Proteins c-myc
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https://hdl.handle.net/10161/4507Published Version (Please cite this version)
10.1371/journal.pone.0003769Publication Info
Wang, J; Wang, H; Li, Z; Wu, Q; Lathia, JD; McLendon, RE; ... Rich, JN (2008). c-Myc is required for maintenance of glioma cancer stem cells. PLoS One, 3(11). pp. e3769. 10.1371/journal.pone.0003769. Retrieved from https://hdl.handle.net/10161/4507.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Roger Edwin McLendon
Professor of Pathology
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant
neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute
the most common solid neoplasm in children and include astrocytomas of the cerebellum,
brain stem and cerebrum as well as medulloblastomas of the cerebellum. My colleagues
and I have endeavored to translate the bench discoveries of genetic mutations and
aberrant protein expressions found in brain tumors to better understan

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