Therapeutic strategies targeting cancer stem cells

Abstract

Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self-renewal, and a multilineage differentiation potential. Cancer stem cells are responsible for the development of tumor cell heterogeneity, a key feature for resistance to anticancer treatments including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Furthermore, minimal residual disease, the major cause of cancer recurrence and metastasis, is enriched in CSCs. Cancer stem cells also possess the property of "robustness", which encompasses several characteristics including a slow cell cycle, the ability to detoxify or mediate the efflux of cytotoxic agents, resistance to oxidative stress, and a rapid response to DNA damage, all of which contribute to the development of therapeutic resistance. The identification of mechanisms underlying such characteristics and the development of novel approaches to target them will be required for the therapeutic elimination of CSCs and the complete eradication of tumors. In this review, we focus on two prospective therapeutic approaches that target CSCs with the aim of disrupting their quiescence or redox defense capability.

Keywords: CD44; Fbw7; intratumoral heterogeneity; niche; plasticity.

Figure 1

Biological characteristics of cancer stem cells. Cancer stem cells possess both self‐renewal ability and multilineage differentiation potential, leading to the composition of intratumoral heterogeneity (a). Cancer stem cells possess the property of “robustness,” which is established by a combination of various phenotypes (b). Cancer stem cells are more resistant to various therapeutic interventions, leading to the generation of minimal residual disease (MRD) that is mainly composed by CSCs, and MRD is a major cause of recurrence and metastasis (c). ABC, ATP‐binding cassette.

Figure 2

Steps in the development of distant metastasis based on cancer stem cell theory. Distant metastasis of tumor cells occurs by way of several distinct steps: dissociation of cancer cells from the primary tumor after they have undergone epithelial–mesenchymal transition (1) is followed by their intravasation (2), circulation in the blood as CTCs (3), extravasation (4), and homing to the premetastatic niche and colonization of the metastatic site (5). Organ‐selective tumor metastasis may depend on whether the premetastatic niche is a favorable microenvironment for circulating cancer stem cells.

Figure 3

Mechanism by which cancer stem cells become quiescent. F‐box and WD40 repeat domain‐containing protein 7 (Fbw7), a subunit of an SCF‐type ubiquitin ligase, negatively regulates cell cycle progression by promoting the ubiquitin‐dependent proteasomal degradation of c‐Myc, Notch, and cyclin E. For instance, leukemia stem cells that lack Fbw7 activity become much more proliferative than hematopoietic stem cells as a result of the accumulation of such driver molecules of the cell cycle. Conversely, upregulation of Fbw7 induces cell cycle arrest, leading to the dormant state of cancer stem cells.

Figure 4

Function of CD44 variant isoform (CD44v) in promoting resistance to oxidative stress. Alternative splicing of the CD44 gene results in the generation of multiple protein isoforms. CD44v8–10 is overexpressed in epithelial cancer stem cells, and their colocalization with the xCT subunit of system Xc(−), a glutamate/cystine antiporter, promotes the uptake of cystine and the consequent synthesis of the antioxidant glutathione, which reduces reactive oxygen species (ROS).