Abstract
Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.
Keywords: Cancer stem cells, differentiation, leukemic stem cells, PI3K/Akt/mTOR, proliferation, targeted therapy, PI3K, Akt, mTOR, CSC biology
Current Medicinal Chemistry
Title: Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cells
Volume: 18 Issue: 18
Author(s): A. M. Martelli, C. Evangelisti, M. Y. Follo, G. Ramazzotti, M. Fini, R. Giardino, L. Manzoli, J. A. McCubrey and L. Cocco
Affiliation:
Keywords: Cancer stem cells, differentiation, leukemic stem cells, PI3K/Akt/mTOR, proliferation, targeted therapy, PI3K, Akt, mTOR, CSC biology
Abstract: Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.
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Cite this article as:
M. Martelli A., Evangelisti C., Y. Follo M., Ramazzotti G., Fini M., Giardino R., Manzoli L., A. McCubrey J. and Cocco L., Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cells, Current Medicinal Chemistry 2011; 18 (18) . https://dx.doi.org/10.2174/092986711796011201
DOI https://dx.doi.org/10.2174/092986711796011201 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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