Heterogeneity of neoplastic stem cells: theoretical, functional, and clinical implications.

Accumulating evidence suggests that human cancers develop through a step-wise, but nonlinear process of cellular diversification and evolution. Recent mutational analyses indicate that this process is more complex and diverse than anticipated before whole-genome sequencing methods were readily available. Examples are also emerging now of genetically abnormal clones of cells that have acquired mutations with known oncogenic potential but, nevertheless, may show no manifestations of malignant change for many years. To accommodate these diverse realities, we suggest the term neoplastic refer to clones of cells that have any type of somatic aberrancy associated with an increased propensity to become malignant, and the derivative term neoplastic stem cell be adopted to identify the cells responsible for the long-term maintenance of such clones. Neoplastic clones would thus include those that never evolve further, as well as those that eventually give rise to fully malignant populations, and all stages in between. The term cancer stem cells would then be more appropriately restricted to cells generating subclones that have established malignant properties. More precise molecular understanding of the different stem cell states thus distinguished should contribute to the development of more effective prognostic and therapeutic tools for cancer diagnosis and treatment.