The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells.
The identification of cancer stem cells in leukemia, breast, brain, colon, and other cancers suggests that many tumors are maintained by stem cells in much the same way as normal tissues are maintained. Because cancer stem cells share remarkable phenotypic and functional similarities with normal stem cells, it may be difficult to identify therapeutic approaches to kill cancer stem cells without killing the normal stem cells in the same tissue. Yet in certain tissues, like the hematopoietic system and gut epithelium, this will be critical as regenerative capacity in these tissues is acutely required for life. Components of the PI-3kinase pathway, including Akt, mTor and FoxO are critical regulators of both normal stem cell function and tumorigenesis. Intriguingly, inactivation of some pathway components, like Pten, has opposite effects on normal hematopoietic stem cells (HSCs) and leukemia-initiating cells. This raises the possibility that drugs targeting this pathway could be more effective at eliminating cancer stem cells while being less toxic against normal stem cells.
Yilmaz
Omer H
OH
Howard Hughes Medical Institute, Department of Internal Medicine, and Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109-2216, USA.
Morrison
Sean J
SJ
D000818:Animals; D016922:Cellular Senescence; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology
D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus