Cancer Stem Cells and Radioresistance: DNA Repair and Beyond

Abstract

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after radiotherapy. In this review, we discuss the molecular mechanisms of CSC radioresistance attributable to DNA repair mechanisms and the development of CSC-targeted therapies for tumor radiosensitization. We also discuss the current challenges in preclinical and translational CSC research including the high inter- and intratumoral heterogeneity, plasticity of CSCs, and microenvironment-stimulated tumor cell reprogramming.

Keywords: 5Rs of radiation biology; DNA repair; cancer stem cells; radioresistance.

Figure 1

The general mechanisms of cancer stem cell (CSC) radioresistance. Many protective mechanisms are activated in CSCs that result in treatment resistance. These include intrinsic determinants (activation of the pro-survival pathways, enhanced DNA repair capability, protection against oxidative stress, unlimited self-renewal potential, impaired cell cycle arrest, and apoptosis) and extrinsic determinants such as hypoxic microenvironment and a protective CSC niche consisting of the cellular components (e.g., non-CSCs, fibroblasts, immune cells, endothelial cells), soluble factors (e.g., growth factors, hormones and cytokines), and extracellular matrix. ATM—ataxia–telangiectasia mutated; ATR—ATM- and Rad3-Related; Chk1—checkpoint kinase 1; Chk2—checkpoint kinase 2; ECM—extracellular matrix; FAK—focal adhesion kinase; GSH—glutathione; JAK—Janus kinase; EGFR—epidermal growth factor receptor; HIF—hypoxia-inducible factor; PI3K—phosphatidylinositol 3-kinases; ROS—reactive oxygen species.

Figure 2

DNA repair pathways altered in CSCs are associated with DNA replication. Replication-associated DNA repair pathways leading to enhanced DNA repair (red) mediate resistance in CSCs, while further replication-associated DNA repair pathways remain unchanged (gray). Upregulation is based on increased expression (red) or increased activation (yellow) or both (red/yellow) and is supported by regulatory proteins (gray). BER—base excision repair; FA—Fanconi anemia; HR—homologous recombination; NER—nucleotide excision repair; NHEJ—non-homologous end joining; MMR—mismatch repair; PR—proof reading; TLS—translesion synthesis [9,68,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85].