Cancer stem cells: understanding tumor hierarchy and heterogeneity

Abstract

Heterogeneity within and between tumors is a well-known phenomenon that greatly complicates the diagnosis and treatment of cancer. A large body of research indicates that heterogeneity develops through time as tumor-initiating stem cells, also known as cancer stem cells (CSCs), evolve genetic or epigenetic alterations that allow them to differentiate into multiple tumor cell types. Similar to normal stem cells, CSCs can self-renew and possess long-term repopulation potential. However, unlike normal stem cells, CSCs are not subject to the usual controls that limit growth. Different models have been postulated to explain the heterogeneity of tumors, but it is widely agreed that interactions between tumor cells and their microenvironment create niches that promote CSC properties and enable their survival. Within the microenvironment, CSC self-renewal, replication, and differentiation are postulated to produce a hierarchy of cells constituting the tumor mass. Increased understanding of the factors that create and contribute to tumor heterogeneity may support the design of therapies that affect CSC function and their microenvironments.

Figure 1

CE (stochastic) vs. CSC (hierarchy) vs. plasticity models—in the CE model, mutations accumulate through time and any cell may have tumorigenic potential.^[6,22] However, this potential cannot be isolated or enriched.^[24] In the CSC model, only stem cells possess tumorigenic potential while differentiated cells have little or none.^[6,22,25] According to the plasticity model, differentiation can be bidirectional so that differentiated nontumorigenic cancer cells may revert back to CSCs. CE = clonal evolution, CSC = cancer stem cell.^[22,23]

Figure 2

Tumor cell hierarchical organization. Tumor cellular hierarchies can vary in depth such that CSCs are relatively rare (top panel), common (middle panel), or even constitute the majority of tumor cells (bottom panel). CSC = cancer stem cell.^[25]