Plasticity in Colorectal Cancer: Why Cancer Cells Differentiate

Simple Summary The cancer stem cell hypothesis postulates that tumors arise from a few cells with self-renewal capabilities. The identification of stem cell markers, the development of mouse and human tumor organoids and their application in mouse models, allowing lineage tracing, helped to better understand the cancer stem cell model as well as the role of differentiation. This review aims at providing insights on the interplay between cancer stem cells and differentiated cells, as well as the importance of plasticity between the two states. The cancer stem cell hypothesis poses that the bulk of differentiated cells are non-tumorigenic and only a subset of cells with self-renewal capabilities drive tumor initiation and progression. This means that differentiation could have a tumor-suppressive effect. Accumulating evidence shows, however, that in some solid tumors, like colorectal cancer, such a hierarchical organization is necessary. The identification of Lgr5 as a reliable marker of normal intestinal epithelial stem cells, together with strategies to trace cell lineages within tumors and the possibility to selectively ablate these cells, have proven the relevance of Lgr5(+) cells for cancer progression. On the contrary, the role of Lgr5(-) cells during this process remains largely unknown. In this review, we explore available evidence pointing towards possible selective advantages of cancer cells organized hierarchically and its resulting cell heterogeneity. Clear evidence of plasticity between cell states, in which loss of Lgr5(+) cells can be replenished by dedifferentiation of Lgr5(-) cells, shows that cell hierarchies could grant adaptive traits to tumors upon changing selective pressures, including those derived from anticancer therapy, as well as during tumor progression to metastasis.

Automated summary

The cancer stem cell hypothesis suggests that tumors originate from a small population of cells with self-renewal capabilities, with differentiated cells potentially having tumor-suppressive effects. Understanding cell hierarchies and plasticity is crucial for investigating the interplay between cancer stem cells and differentiated cells.