Tumor-initiating and -propagating cells: cells that we would like to identify and control.

Identification of the cell types capable of initiating and sustaining growth of the neoplastic clone in vivo is a fundamental problem in cancer research. It is likely that tumor growth can be sustained both by rare cancer stem-like cells and selected aggressive clones and that the nature of the mutations, the cell of origin, and its environment will contribute to tumor propagation. Genomic instability, suggested as a driving force in tumorigenesis, may be induced by genetic and epigenetic changes. The feature of self-renewal in stem cells is shared with tumor cells, and deviant function of the stem cell regulatory networks may, in complex ways, contribute to malignant transformation and the establishment of a cancer stem cell-like phenotype. Understanding the nature of the more quiescent cancer stem-like cells and their niches has the potential to develop novel cancer therapeutic protocols including pharmacological targeting of self-renewal pathways. Drugs that target cancer-related inflammation may have the potential to reeducate a tumor-promoting microenvironment. Because most epigenetic modifications may be reversible, DNA methylation and histone deacetylase inhibitors can be used to induce reexpression of genes that have been silenced epigenetically. Design of therapies that eliminate cancer stem-like cells without eliminating normal stem cells will be important. Further insight into the mechanisms by which pluripotency transcription factors (e.g., OCT4, SOX2, and Nanog), polycomb repressive complexes and microRNA balance selfrenewal and differentiation will be essential for our understanding of both embryonic differentiation and human carcinogenesis and for the development of new treatment strategies.