Cancer immunology. Bench to bedside immunotherapy of cancers. Nima Rezaei (Ed.). Springer-Verlag (2015)
At present, CSCs are suggested to be those cells, usually sorted by flow cytometry on the basis of the expression of a particular cell surface marker, that have the tumorigenic ability to form a new tumor in an in vivo xenograft assay and/or ability to form cell spheres when plated at low density in nonadherent culture . Despite this broad definition, it is still hard to define CSCs as a single universal entity, suggesting that the CSC phenotype may vary substantially across different tumors and, more interestingly, could not fit to a steady definition across the natural history of cancer. Experimental observations led to the hypothesis that “stemness” may not be a fixed “immutable” property, but rather a more dynamic condition, with cells evolving to more or less differentiated states [146–148]. Indeed, it has been suggested that CSCs can undergo reversible fluctuations in their stem cell status [149–151]. These findings account for the possibility that cancer stemness can be acquired by modification in the gene expression programs. Although the molecular pathways underlying these effects are largely unknown, the concept of phenotypic reversion suggests the presence of a balance between CSCs and differentiated cells. Moreover, in recent years, multiple studies confirmed the presence of an important degree of intra-tumor heterogeneity, with several clones coexisting in the same tumor mass , resulting from genetic instability. Two major, not mutually exclusive, mechanisms explain intratumoral heterogeneity :
- Different genetic or epigenetic mutations occurring within the same target
- Different tumor subtypes arising from distinct clones within the same tissue 
These observations turn our traditional view of the CSC model from a “hierarchical” structure (a cancer stem cell on the top of a differentiated tumor cell population) to an “oligarchic” structure with multiple genetically different cell lineages competing with each other , in particular in advanced stage disease where cancer therapy exerts a powerful selective pressure on cancer cells.