Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis.

The concept of cancer stem cells (CSC) embodies two aspects: the stem cell as the initial target of the oncogenic process and the existence of two populations of cells in cancers: the CSC and derived cells. The second is discussed in this review. CSC are defined as cells having three properties: a selectively endowed tumorigenic capacity, an ability to recreate the full repertoire of cancer cells of the parent tumor and the expression of a distinctive repertoire of surface biomarkers. In operational terms, the CSC are among all cancer cells those able to initiate a xenotransplant. Other explicit or implicit assumptions exist, including the concept of CSC as a single unique infrequent population of cells. To avoid such assumptions, we propose to use the operational term tumor-propagating cells (TPC); indeed, the cells that initiate transplants did not initiate the cancer. The experimental evidence supporting the explicit definition is analyzed. Cancers indeed contain a fraction of cells mainly responsible for the tumor development. However, there is evidence that these cells do not represent one homogenous population. Moreover, there is no evidence that the derived cells result from an asymmetric, qualitative and irreversible process. A more general model is proposed of which the CSC model could be one extreme case. We propose that the TPC are multiple evolutionary selected cancer cells with the most competitive properties [maintained by (epi-)genetic mechanisms], at least partially reversible, quantitative rather than qualitative and resulting from a stochastic rather than deterministic process.