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.
Highlights
According to the global cancer statistics, cancer incidence and mortality are increasing worldwide with an estimated 29 million new cancer cases by 2030 [1,2,3,4], attributed to constant growth and aging of the human population [5]
Identification of markers for the detection of tumor-initiating cells, first in leukemia by the group of John Dick (CD 34+ /CD38− ) and in solid tumors including glioma (CD133+, aldehyde dehydrogenase, ALDH1+ ), breast, colorectal (CD133+, EpCAMhigh /CD44+, ALDH1+ ), head and neck squamous carcinoma (CD44+ ), and other cancers as discussed elsewhere [21], paved the way for isolating, enriching, and analyzing these tumorigenic cells in different tumor entities [15,21,22]. These findings indicated that tumor-initiating cells, called cancer stem cells (CSCs) possess two fundamental properties that make them different from other tumor cells; they have unlimited capacity to self-renew and differentiate to all cell populations present in the original tumors
Assuming that DNA repair pathways are upregulated in CSCs, and that radiation or genotoxic substances themselves lead to increased CSC accumulation, amplified DNA repair pathways should be inhibited in parallel to radiochemotherapy
Summary
According to the global cancer statistics, cancer incidence and mortality are increasing worldwide with an estimated 29 million new cancer cases by 2030 [1,2,3,4], attributed to constant growth and aging of the human population [5]. Identification of markers for the detection of tumor-initiating cells, first in leukemia by the group of John Dick (CD (cluster of differentiation) 34+ /CD38− ) and in solid tumors including glioma (CD133+ , aldehyde dehydrogenase, ALDH1+ ), breast (epithelial cell adhesion molecule, EpCAM+ /CD44high /CD24low , ALDH1+ ), colorectal (CD133+ , EpCAMhigh /CD44+ , ALDH1+ ), head and neck squamous carcinoma (CD44+ ), and other cancers as discussed elsewhere [21], paved the way for isolating, enriching, and analyzing these tumorigenic cells in different tumor entities [15,21,22] These findings indicated that tumor-initiating cells, called cancer stem cells (CSCs) possess two fundamental properties that make them different from other tumor cells; they have unlimited capacity to self-renew (e.g., divide asymmetrically to produce an identical copy of itself and more differentiated progeny cells) and differentiate to all cell populations present in the original tumors. We discuss the preclinical investigation of the CSC role in tumor radioresistance, clinical evidence for CSCs as potential prognosticators and therapeutic targets in radiation oncology, and potential challenges for their translation into clinical practice
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