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Review
. 2016:2016:1740936.
doi: 10.1155/2016/1740936. Epub 2016 Jun 21.

Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy

Wanyin Chen  1 , Jihu Dong  1 , Jacques Haiech  1 , Marie-Claude Kilhoffer  1 , Maria Zeniou  1
Affiliations
Review

Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy

Wanyin Chen et al. Stem Cells Int. 2016.

Abstract

Cells with stem-like properties, tumorigenic potential, and treatment-resistant phenotypes have been identified in many human malignancies. Based on the properties they share with nonneoplastic stem cells or their ability to initiate and propagate tumors in vivo, such cells were designated as cancer stem (stem-like) or tumor initiating/propagating cells. Owing to their implication in treatment resistance, cancer stem cells (CSCs) have been the subject of intense investigation in past years. Comprehension of CSCs' intrinsic properties and mechanisms they develop to survive and even enhance their aggressive phenotype within the hostile conditions of the tumor microenvironment has reoriented therapeutic strategies to fight cancer. This report provides selected examples of malignancies in which the presence of CSCs has been evidenced and briefly discusses methods to identify, isolate, and functionally characterize the CSC subpopulation of cancer cells. Relevant biological targets in CSCs, their link to treatment resistance, proposed targeting strategies, and limitations of these approaches are presented. Two major aspects of CSC physiopathology, namely, relative in vivo quiescence and plasticity in response to microenvironmental cues or treatment, are highlighted. Implications of these findings in the context of the development of new therapies are discussed.

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Figures

Figure 1
Figure 1
Cancer stem cell (CSC) properties and experimental methods for phenotypic and functional characterization of CSCs. (a) CSCs express cell surface antigens (CD133, CD34, and CD44) and signaling molecules (OCT4, NANOG, and SOX2) linked to a stem-like phenotype. CD: cluster of differentiation; OCT-4: octamer-binding transcription factor 4. (b) CSCs possess clonal properties and may be maintained in vitro for long intervals in serum-free medium. Under these conditions, they are able to form clonal tumorospheres. (c) CSCs present increased Hoechst efflux capacity compared to normal cells. Based on this property, they are designated as the side population (SP). (d) Multilineage differentiation (in the presence of serum) is another property of CSCs. Differentiation ability is verified by the decrease in the expression of stem cell markers accompanied by an increase in the expression of differentiation markers. Differentiated cells lose their tumorigenic potential. (e) CSCs at limiting dilutions are able to generate tumors after serial xenografting into immunocompromised mice. These tumors recapitulate the characteristics of the tumor from which CSCs were derived. Figure was constructed in part with objects from Servier Medical Art documents under license from Creative Commons Attribution 3.0 France (http://creativecommons.org/licenses/by/3.0/fr/legalcode).
Figure 2
Figure 2
Mechanisms of CSCs' therapy resistance and relevant biological targets. ((a)-(b)) Increased self-renewal and prosurvival signaling have been reported for CSCs. Molecules involved in self-renewal/survival as well as antiapoptotic proteins overexpressed in CSCs are potentially interesting targets for therapies seeking CSC elimination. Hh: Hedgehog; SMO: Smoothened; Ptch1: Patched; Dll: Delta-like ligand; Wnt: wingless integration site; Fz: Frizzled; LRP: low-density lipoprotein receptor-related protein; BMI1: polycomb ring finger; BCL-XL: B-cell lymphoma extra-large; BCL2: B-cell lymphoma 2. (c) CSCs respond with higher efficacy to DNA damage via checkpoint arrest for longer time intervals and enhanced DNA repair. Moreover, reduced levels of ROS have been reported in CSCs leading to protection of the CSC genome from DNA damage. Proteins involved in checkpoint arrest, DNA repair, and intracellular redox balance are relevant biological targets in CSCs. (d) Increased expression/function of ABC transporters in CSCs underlies more efficient drug efflux from these cells. ABC transporters are thus interesting therapeutic targets in CSCs. (e) Tumor initiation and propagation properties of CSCs involve their stem-like phenotype. Signaling modules involved in the maintenance of this state are relevant targets for CSC elimination. CD: cluster of differentiation; OCT-4: octamer-binding transcription factor 4. (f) Quiescent CSCs have been evidenced in many human malignancies and are major determinants of CSCs' resistance to current treatments. Neutralization of the CSC quiescent phenotype is a promising approach for new anticancer protocols. (g) Induced CSC-like phenotypes may be obtained by the action of signals from the tumor microenvironment and/or as a result of therapy. Cell plasticity observed in human malignancies must be taken into account when developing new anticancer therapies. Figure was constructed in part with objects from Servier Medical Art documents under license from Creative Commons Attribution 3.0 France (http://creativecommons.org/licenses/by/3.0/fr/legalcode).
Figure 3
Figure 3
Strategies proposed for neutralization of the CSC quiescent phenotype involved in treatment resistance. Three strategies have been proposed to neutralize the quiescent CSC-state. Induction of CSC entry into the cell cycle would sensitize cells to antiproliferating agents. Blocking quiescent CSCs in G0 was proposed as an alternative for preventing new tumor growth. Targeting CSCs in the quiescent state was also proposed for the elimination of this particular CSC subpopulation. CSC: cancer stem cell. Figure was constructed in part with objects from Servier Medical Art documents under license from Creative Commons Attribution 3.0 France (http://creativecommons.org/licenses/by/3.0/fr/legalcode).
Figure 4
Figure 4
Mechanisms inducing CSC phenotypes. The CSC phenotype of cancer cells is influenced by cues related to the tumor microenvironment. These include remodeling of the extracellular matrix and signaling through factors secreted by endothelial, immune system cells and stromal fibroblasts. Signaling related to EMT (epithelial to mesenchymal transition) may also induce a CSC phenotype. Low oxygen (hypoxia) and acidic conditions nearby the CSC niche may induce and/or enhance the CSC phenotype of cells. Radiotherapy and chemotherapy have been shown to induce dedifferentiation of cancer cells and acquisition of a CSC phenotype. Figure was constructed in part with objects from Servier Medical Art documents under license from Creative Commons Attribution 3.0 France (http://creativecommons.org/licenses/by/3.0/fr/legalcode).
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