Identification and targeting of cancer stem cells

Abstract

Cancer stem cells (CSC) represent malignant cell subsets in hierarchically organized tumors, which are selectively capable of tumor initiation and self-renewal and give rise to bulk populations of non-tumorigenic cancer cell progeny through differentiation. Robust evidence for the existence of prospectively identifiable CSC among cancer bulk populations has been generated using marker-specific genetic lineage tracking of molecularly defined cancer subpopulations in competitive tumor development models. Moreover, novel mechanisms and relationships have been discovered that link CSC to cancer therapeutic resistance and clinical tumor progression. Importantly, proof-of-principle for the potential therapeutic utility of the CSC concept has recently been provided by demonstrating that selective killing of CSC through a prospective molecular marker can inhibit tumor growth. Herein, we review these novel and translationally relevant research developments and discuss potential strategies for CSC-targeted therapy in the context of resistance mechanisms and molecular pathways preferentially operative in CSC.

Figure 1

The cardinal features of CSC. CSC are characterized by three defining properties: (1) enhanced capacity for proliferation and tumorigenic growth, (2) long-term self-renewal ability, and (3) potential to give rise to more differentiated tumor bulk populations devoid of CSC characteristics. These cardinal CSC features can be attributed to molecularly defined cancer subpopulations using in vivo genetic lineage tracking in competitive tumor development models.

Figure 2

Conventional therapies versus CSC-targeted therapeutic strategies. A: conventional tumor therapies may initially shrink cancers by killing mainly tumor bulk populations with limited self-renewal and proliferative potential. Resistant CSC may remain viable after treatment and ultimately reestablish tumor growth, leading to relapse and neoplastic progression. B: In contrast, novel CSC-targeted approaches strip the tumor of its capacity to generate cancer cell progeny, which inhibits tumor growth and might ultimately result in tumor degeneration.