Cancer Stem Cells Can Arise From Differentiated Neoplastic Cells

Although the concept of a hierarchical origination of cancer has existed for several decades, recently the cancer stem cell (CSC) hypothesis has become popular. Instead of each tumor cell possessing similar tumor initiating capacity, the CSC model is appealing because it offers an alternative way to appreciate the cellular organizational structure of a tumor—if true, could have major therapeutic implications. It suggests that clinical progression and tumor recurrence originate not from a failure of maximal neoplastic cell inhibition, but the failure of targeting the CSC that sits at the apex of a cellular hierarchy and is the escape tumor cell(s) representing the seed of clinical failure. Important to note, CSC designation does not suggest that CSCs originate from normal stem cells, only that these malignant cells display stem features (ability to differentiate, self renewal and recapitulation of original tumors upon xenotransplanation with limited number of cells). As investigation into CSCs has expanded, limitations have arisen. Indeed the CSC model is not applicable to all tumor types and the fraction of tumor cells that are “true” CSC may be difficult to define, since experimental parameters can lead to highly different ratios of the CSC and non-CSC tumor fraction. Nevertheless, several models of tumor formation and perpetuation may not be mutually exclusive and alternatively a tumor may employ both models (stochastic, hierarchical) to achieve evolutionary success. But what if CSCs are a dynamic state and inter-conversion between non-CSC and CSC exists? Chaffer et al (PNAS, 2011)from the Weinberg group identified a subpopulation of basal-like human mammary epithelial cells that spontaneously dedifferentiate into stem-like cells. Oncogenic transformation enhanced the observed spontaneous conversion, so that non-stem cancer cells give rise to cancer stem cell-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of post-transformation behavior. Their findings demonstrate that CSC can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional inter-conversions between stem and nonstem compartments (Figure 2 from paper). The greatest appeal of the CSC model lies in the potential to target a limited subpopulation of cells that are responsible for tumor propagation. The data presented by Chaffer et al raise a major concern regarding the efficacy of a therapeutic strategy targeting CSCs. If CSCs are inhibited, but non-CSCs can repopulate the CSC fraction by inter-conversion, this would present a major obstacle for clinical application since there is no “permanent” CSC. These and other data in molecular biology of cancer remind us of the heterogeneity that exists in tumors, akin to an oncologic ecosystem where cells dynamically employ multiple mechanisms for maximal biological fitness. Rahul Jandial Dawn J. Waters Mike Y. Chen