Therapeutic implications of the cancer stem cell hypothesis

Abstract

A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. The existence of CSCs mandates careful analysis and comparison of normal tissue stem cells and CSCs to identify differences between the two cell types. The development of CSC-targeted treatments will face a number of potential hurdles, including normal stem cell toxicity and the acquisition of treatment resistance, which must be considered in order to maximize the chance that such therapies will be successful.

Figure 1. Implications of the CSC hypothesis for cancer treatment

Conventional cytotoxic therapies can shrink tumors, but may preferentially spare some CSC. Since CSC are left behind, tumors will eventually regrow. However, CSC-targeted therapies could remove the self-renewing tumor cells and thus lead to tumor stabilization and likely eventual regression.

Figure 2. Identifying CSC-specific therapeutic targets

Isolation of CSC allows comparison of CSC to their non-tumorigenic counterparts and to normal tissue stem cells. This facilitates the development of CSC-specific therapies. FACS- fluorescent activated cell sorting.

Figure 3. Overcoming resistance to CSC-directed therapies

Genomic instability within CSC likely results in CSC subclones, some of which may harbor genetic changes that make them partially resistant to a given CSC-specific therapy. Therefore, treatment with a CSC-specific therapeutic may fail due to selection for resistant CSC. However, multimodality approaches which combine conventional cytotoxic agents and CSC-specific therapies may overcome this problem. While CSC may be partially resistant to either modality, their combined effects could lead to the elimination of all CSC. This approach has the additional benefit of rapidly debulking tumors due to the effect of cytotoxic therapies on non-tumorigenic cells.