Regulation of cancer stem cells by p53

The recent identification and characterization of stem cells in a variety of adult tissues has led to renewed interest in the role of stem cells in cancers. Cancer stem cells are hypothesized to be a small population of cells within a tumor that are capable of self-renewal and that can undergo differentiation to generate the phenotypic heterogeneity observed in tumors. Contemporary methods for studying cancer stem cells have most often used cell surface markers to enrich the subset of cells capable of initiating a tumor upon transplantation into an appropriate host. Molecular pathways that limit expansion of the tumor-initiating cell population could be targeted to eradicate tumors.Using mammary tumors arising spontaneously from transplants of BALB/c-Trp53-/- mammary epithelium, Zhang and coworkers show that cells expressing markers of mouse mammary stem cells (lin-/CD29hi/CD24hi) had a greater tumor-initiating frequency [1]. This observation was consistent among tumors with heterogeneous expression of markers for the luminal epithelium and the basal epithelium. The lin-/CD29hi/CD24hi population shared additional features of mammary stem cells, including radiation resistance and the formation of secondary mammospheres.But how might loss of p53 lead to formation or expansion of the tumor-initiating pool? Using a unique culture model of luminal breast epithelial cells (BPEC-T), Godar and coworkers demonstrate that p53 binds to the promoter of CD44 [2], a commonly used marker of cancer stem cells [3], and represses CD44 expression. Constitutive expression of CD44 blocked p53-dependent apoptosis and rendered cells resistant to doxorubicin. Conversely, suppression of CD44 expression restricted tumor-initiating cells.These results link the loss of p53 function to increased expression of CD44, which promotes expansion of tumor-initiating cells purified in tumors. The p53 protein appears to play a similar role in embryonic stem cells, where p53 represses expression of Nanog