Bidirectional interconversion of stem and non-stem cancer cell populations: A reassessment of theoretical models for tumor heterogeneity

Resolving the origin of intratumor heterogeneity has proven to be one of the central challenges in cancer research during recent years. Two theoretical models explaining the emergence of intratumor heterogeneity have come to dominate cancer biology literature: the clonal evolution model and the hierarchical/cancer stem cell model. Recently, a plastic model that combines elements of both the clonal and the hierarchical model has gained traction. Basically, this model proposes that cancer stem cells engage in bidirectional interconversion with non-stem cells, thereby providing the missing link between the 2 conventional models. Confirming bidirectional interconversion as a hallmark of cancer is a crucial step in understanding tumor heterogeneity and has important therapeutic implications. In this review, current methodologies and theoretical and empirical evidence regarding bidirectional interconversion will be discussed.