c-Myc Is Required for Maintenance of Glioma Cancer Stem Cells
Open Access
- 20 November 2008
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 3 (11), e3769
- https://doi.org/10.1371/journal.pone.0003769
Abstract
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. 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 G0/G1 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. 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.Keywords
This publication has 63 references indexed in Scilit:
- MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancerNature, 2004
- Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasiaOncogene, 2004
- Role of E2F1 in apoptosis: a case study in feedback loops.Cell Cycle, 2004
- Identification of a cancer stem cell in human brain tumors.2003
- Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocationsBlood, 2003
- Prospective identification of tumorigenic breast cancer cellsProceedings of the National Academy of Sciences, 2003
- Astroglial c-Myc Overexpression Predisposes Mice to Primary Malignant GliomasJournal of Biological Chemistry, 2003
- Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYCScience, 2002
- Deregulated expression of c-Myc depletes epidermal stem cellsNature Genetics, 2001
- c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutationsNature Medicine, 2001