The CDK inhibitors: potential targets for therapeutic stem cell manipulations?

Therapies involving adult stem cells are dependent upon sufficient expansion of these cells to repopulate or replace the diseased tissue and are consequently hindered by their relatively quiescent phenotype. Cellular proliferation is governed by the cyclin-dependent kinases, which in a complex with a corresponding cyclin, phosphorylate a number of downstream mediators to drive the cell through the cell cycle. In turn, biochemical activities of the cyclin-dependent kinases are regulated by two families of cyclin-dependent kinase inhibitors, which have been shown to be potent cell intrinsic blocks of adult stem cell proliferation in multiple tissue types. In contrast to normal stem cells, inappropriate regulation of the cell cycle in cancer stem cells may underlie tumorigenesis and failure of conventional chemotherapeutics to fully eradicate a tumor. Thus, definition of the roles of the cyclin-dependent kinase inhibitors in normal and cancer stem cells may permit the development of novel strategies for adult stem cell expansion and therapies specifically targeted to cancer stem cells.