TGF-β, notch, and wnt in normal and malignant stem cells: Differentiating agents and epigenetic modulation

The notion that the growth and so-called aberrant differentiation of many tumors depend on the existence of a small population of cancer stem cells in much the same way that organogenesis and tissue replacement depend on normal stem cells is at the heart of contemporary investigations of neoplastic diseases. Not surprisingly, the same genetic and signaling pathways that are involved in normal stem cell renewal and specification are also important in tumorigenesis. These pathways include the Wnt/β-catenin, Notch, and TGF-β signaling systems, all of which have been reviewed recently. In this chapter, we will highlight areas that are either developing or have not been covered extensively in other reviews. For example, recent studies have highlighted a role for the RNA binding protein Musashi 1 (Msi1) in the regulation of normal and cancer stem cells through the Wnt and Notch pathways. Notch and Wnt signaling also regulate and are regulated by asymmetric cell division, a defining stem cell characteristic that has received little attention in the cancer stem cell literature. Asymmetric cell division, which results in the segregation of damaged proteins into only one of the daughter cells, has also recently been linked to stem cell aging, a process that clearly differs between normal and cancer stem cells. The ability of carcinoma cells to take on characteristics typical of cells from quite different backgrounds is well established and almost certainly related to a pluripotent stem cell–like origin.