Abstract
BackgroundMalignant 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 FindingsBased 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.Conclusions/SignificanceThese 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.
Highlights
The emerging cancer stem cell model suggests that tumors are organized in a hierarchy with a subpopulation of cancer stem cells responsible for tumor maintenance and progression
To directly measure the expression of c-Myc in human brain tumors, we further evaluated c-Myc expression by flow cytometry in both CD133+ and CD1332 fractions of glioma cells acutely isolated from human surgical biopsy specimens without in vitro culture (Figure 1C)
Glioma cancer stem cells enriched by selection of the CD133 surface antigen form orthotopic xenograft tumors with 500 cells in athymic nude mice, whereas 26106 CD1332 cells cannot [9]
Summary
The emerging cancer stem cell model suggests that tumors are organized in a hierarchy with a subpopulation of cancer stem cells responsible for tumor maintenance and progression. The cancer stem cell population contributes to solid tumor angiogenesis [3], metastasis [4], and resistance to chemotherapy and radiotherapy [3,5,6,7,8,9] While this model has been validated in a growing list of haematopoietic and solid tumors, the molecular signaling pathways orchestrating the biology of cancer stem cells remain to be elucidated. Excluding c-Myc from this combination without eliminating endogenous c-Myc expression, drastically reduces the efficiency of iPS cell production [13,14,15,16] While all of these data suggest a role for c-Myc in maintaining stem cells, other functions of c-Myc in regulating stem cell biology have been described. 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
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