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.
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