期刊
STEM CELLS
卷 26, 期 12, 页码 3027-3036出版社
WILEY
DOI: 10.1634/stemcells.2007-1073
关键词
Glioma; Akt; Targeted therapy; Small molecule inhibitor; Cancer stem cell
资金
- Childhood Brain Tumor Foundation
- Pediatric Brain Tumor Foundation of the United States
- Accelerate Brain Cancer Cure
- Alexander and Margaret Stewart Trust
- Brain Tumor Society
- Goldhirsh Foundation
- Duke Comprehensive Cancer Center Stem Cell Initiative
- NIH [NS047409, NS054276, CA129958, CA116659]
- Damon Runyon Cancer Research Foundation
- Sidney Kimmel Foundation for Cancer Research Scholar
- National Institute of General Medical Sciences [2T32GM007171]
- NATIONAL CANCER INSTITUTE [R01CA129958, R01CA116659] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007171] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS054276, K02NS047409] Funding Source: NIH RePORTER
Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies. STEM CELLS 2008; 26: 3027-3036
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