A. M. Martelli, C. Evangelisti, M. Y. Follo, G. Ramazzotti, M. Fini, R. Giardino, L. Manzoli, J. A. McCubrey and L. Cocco Pages 2715 - 2726 ( 12 )
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.
Cancer stem cells,differentiation,leukemic stem cells,PI3K/Akt/mTOR,proliferation,targeted therapy,PI3K,Akt,mTOR,CSC biology
, , , , , , , , Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Universita di Bologna, via Irnerio 48, 40126 Bologna, Italy.