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

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).

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