Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cells
A. M. Martelli, C. Evangelisti, M. Y. Follo, G. Ramazzotti, M. Fini, R. Giardino, L. Manzoli, J. A. McCubrey and L. Cocco
Affiliation: Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Universita di Bologna, via Irnerio 48, 40126 Bologna, Italy.
Keywords: Cancer stem cells, differentiation, leukemic stem cells, PI3K/Akt/mTOR, proliferation, targeted therapy, PI3K, Akt, mTOR, CSC biology
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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