Cancer stem cell-directed therapies: recent data from the laboratory and clinic

Abstract

Cancer stem cells (CSCs) are defined by their ability to (i) fully recapitulate the tumor of origin when transplanted into immunodeficient mouse hosts, and (ii) self-renew, demonstrated by their ability to be serially transplanted. These properties suggest that CSCs are required for tumor maintenance and metastasis; thus, it has been predicted that CSC elimination is required for cure. This prediction has profoundly altered paradigms for cancer research, compelling investigators to prospectively isolate CSCs to characterize the molecular pathways regulating their behavior. Many potential strategies for CSC-directed therapy have been proposed, but few studies have rigorously demonstrated their efficacy using in vivo models. Herein, we highlight recent studies that demonstrate the utility of CSC-directed therapies and discuss the implications of the CSC hypothesis to experimental design and therapeutic strategies.

Figure 1

Strategies to evaluate CSC-directed therapy in preclinical models. Top: Treat bulk tumor or CSCs in vitro, then measure the therapeutic effect in vitro. Parameters to be measured include (i) decreased growth/increased cell death, (ii) CSC selectivity, and (iii) differentiation. Top: Pretreat bulk tumor or purified CSCs in vitro followed by transplantation. Parameters to be measured include level of engraftment (tumor burden), frequency of CSCs, and durability of effect. Ideally, transplanted mice should be monitored serially. Bottom: Treatment of previously engrafted tumors in vivo. Parameters to be measured include tumor growth/reduction, differentiation status, durability of effect, and ability of any residual disease to serial transplant. Ideally, serial transplants should be performed with equivalent numbers of tumor cells, either bulk or purified CSCs, to determine whether or not the effect of a drug is at the level of single cells or entire tumor cell populations.

Figure 2

Potential CSC therapeutic strategies. CSC-directed therapeutic strategies may include stand-alone and combination therapies. (a) The CSC hypothesis predicts that conventional therapies fail to target CSCs, resulting in disease relapse. CSC therapies may exert a direct cytotoxic effect on CSCs or by inducing differentiation. (b) Combination therapies involve using conventional therapies or novel sensitizing agents in combination with CSC-directed therapies. Please refer to the text for descriptions of the cited examples.