Brain cancer stem cells display preferential sensitivity to Akt inhibition.
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.
Eyler
Christine E
CE
School of Medicine, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham North Carolina, USA.
Foo
Wen-Chi
WC
LaFiura
Katherine M
KM
McLendon
Roger E
RE
Hjelmeland
Anita B
AB
Rich
Jeremy N
JN
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D000071916:AC133 Antigen; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt
Oncogene. 2008 Mar 13;27(12):1749-58
17891174
Nat Clin Pract Neurol. 2007 Dec;3(12):682-93
18046441
Cell Stem Cell. 2007 Oct 11;1(4):389-402
18371377
Stem Cell Rev. 2008 Sep;4(3):203-10
18595010
Nat Genet. 2000 May;25(1):55-7
10802656
Cancer Res. 2001 Sep 15;61(18):6674-8
11559533
Science. 2001 Dec 7;294(5549):2186-9
11691952
Cancer Res. 2002 Oct 1;62(19):5551-8
12359767
Cancer Res. 2003 Sep 15;63(18):5821-8
14522905
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83
14645703
Curr Opin Genet Dev. 2004 Feb;14(1):43-7
15108804
Cancer Res. 2004 Oct 1;64(19):7011-21
15466194
Nature. 2004 Nov 18;432(7015):396-401
15549107
Science. 2005 Feb 18;307(5712):1098-101
15718470
Mol Cell. 2005 Apr 15;18(2):143-5
15837416
Cancer Res. 2005 Aug 15;65(16):7052-8
16103051
Neuropathol Appl Neurobiol. 2005 Oct;31(5):486-90
16150119
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):111-6
16373498
Cancer Res. 2006 Feb 1;66(3):1500-8
16452206
Cancer Res. 2006 Aug 15;66(16):7843-8
16912155
Nat Med. 2006 Oct;12(10):1167-74
16998484
Folia Neuropathol. 2006;44(3):214-20
17039417
Cancer. 2006 Nov 15;107(10):2446-54
17041888
Nature. 2006 Dec 7;444(7120):756-60
17051156
Mol Cancer. 2006;5:67
17140455
Annu Rev Med. 2007;58:267-84
17002552
Cancer Cell. 2007 Jan;11(1):69-82
17222791
Cancer Res. 2007 May 1;67(9):4010-5
17483311
Cancer Res. 2007 May 1;67(9):4287-94
17483341
Int J Oncol. 2007 Oct;31(4):753-60
17786305
J Biol Chem. 2007 Sep 14;282(37):27020-9
17631503
Mol Cancer Ther. 2007 Sep;6(9):2449-57
17766837
Int J Cancer. 2008 Feb 15;122(4):761-8
17955491
Biochim Biophys Acta. 2008 Jan;1784(1):150-8
17964232
Genes Dev. 2008 Feb 15;22(4):436-48
18281460
Neurol Clin. 2007 Nov;25(4):1111-39, x
17964028
Cell Stem Cell. 2007 Sep 13;1(3):313-23
18371365