Deciphering tumor growth by clonal analysis

One of the key goals of cancer research is to understand more precisely the mechanisms of tumor growth. It has been hypothesized for several decades that some tumors may be hierarchically organized as normal tissues. Many studies have suggested the existence of cancer stem cells (CSCs) at the top of the cellular hierarchy in tumors. The proof of concept for the existence of the CSC model has been demonstrated by the ability of particular tumor cells to reform tumor growth upon transplantation into severely immunodeficient mice. CSCs have been described in many different human cancers and have been hypothesized to sustain tumor growth, to resist chemo- and radiotherapy, and to be responsible for tumor relapse. While these studies clearly show the differential potential of cancer cells in these experimental conditions and demonstrate functional intratumoral heterogeneity, they do not necessarily reflect the actual fate of tumor cells in their native environment; the existence of CSCs during unperturbed tumor growth remained unproven for a long time. Different recent reports used clonal analysis and lineage tracing tools to demonstrate the hierarchical organization of tumors in vivo in unperturbed colon and skin cancer models. This review discusses the unique opportunities opened through the use of tracing methods to further characterize CSCs in different tumor models as well as their utility in dissecting the mechanism of action of new therapeutics targeting specifically CSCs.