Cancer Stem Cells and Tumor Microenvironment in Radiotherapy

Part of the Cancer Treatment and Research book series (CTAR)


Ionizing radiation (IR) began to be a powerful medical modality soon after Wilhelm Röntgen’s discovery of X-rays in 1895. Today about 60% of cancer patients worldwide receive radiotherapy in their course of cancer control. In the past decades, the technology for precisely delivering tumor IR dose such as stereotactic body radiation therapy (SBRT) has been significantly enhanced, which increases the overall local tumor response and clinical benefit. However, in achieving the goal for long-term cancer control, radiotherapy (RT) has faced several major challenges including the elucidation of the microenvironment causing tumor repopulation and resistance, especially with the most aggressive tumor cells in late phase metastatic lesions. To meet this challenge, a great deal of effort has been devoted to revealing not only the mechanistic insight of tumor heterogeneity, but also the emerging complexity of the irradiated microenvironment. Such new knowledge provides the explanation for the long recognized tumor heterogeneity and tumor cell repopulation, one the major “R”s in tumor radiobiology, which involves cancer stem cells (also termed tumor-imitating cells, cancer stem-like cells, or stem like cancer cells). It is generally accepted that CSCs plays a key role in tumor adaptive radioresistance and are involved in clinical tumor response. The specific cell surface biomarkers as well as the biological topographies of CSCs in many solid tumors have been identified; some of them overlap with those detected in normal stem cells. However, the exact molecular mechanism causing the radioresistant phenotype of CSCs, especially the dynamic nature of CSCs themselves under RT and their communication with the irradiated tumor microenvironment including stromal cells and immune cells, remains to be elucidated. Further elucidation of the complexity of the irradiated local tumor microenvironment in which CSCs reside may generate significant new information to resensitize radioresistant tumor cells and thus to improve therapeutic efficacy. In this chapter, I will describe the general information on normal stem cells, CSCs, CSCs-associated tumor repopulation and energy reprogramming and potential therapeutic targets. The dynamic features of radioresistance-associated factors such as NF-κB and HER2 in some CSCs including breast cancer and GBM will be discussed.


Tumor resistance Radiotherapy Microenvironment Cancer stem cells Tumor repopulation Metabolic reprogramming Immunoresponse Radiosensitization 



Aldehyde dehydrogenase


All-trans retinoic acid


Adenosine triphosphate


Breast cancer stem cells


Cyclin-dependent kinases 1


Cyclin-dependent kinases 2


Checkpoint kinase 1


Checkpoint kinase 1


Cancer stem cells


Chemokine C-X-C motif receptor 4


Epithelial–mesenchymal transition


Embryonic stem cells


Fatty acid oxidation


Fractionated ionizing radiation


Fractionated radiation


Glioblastoma multiforme


Glioblastoma multiforme stem cells


Hypoxia inducible factor alpha


Hematopoietic stem cells


IR-induced immunogenic cell death


Induced pluripotent stem cells


Ionizing radiation


IR-induced immunogenic cell death


Lactate dehydrogenase


Nuclear factor kappa B


Normal stem cells; neural stem cells


Manganese-containing superoxide dismutase


Reactive oxygen species


Stereotactic body radiation therapy


Oxidative phosphorylation


Radiation therapy


Triple-negative breast cancer



I regret not being able to cite all the important work done in this area due to space restrictions. I’d like to take this opportunity to thank the invaluable input and discussions from all of my colleagues, collaborators and friends who contributed many novel concepts to my research. I thank the graduate students, postdoctoral fellows, and lab personnel who have been involved in the research projects and performed the major of research work in my lab. The author also acknowledges grant support from the National Institutes of Health RO1 CA133402 and CA152313.


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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Radiation Oncology, School of MedicineNCI-Designated Comprehensive Cancer Center, University of California DavisSacramentoUSA

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