. 2020 Jul; 9(7):1651.
doi: 10.3390/cells9071651.

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

María Auxiliadora Olivares-Urbano 1 Carmen Griñán-Lisón 2 Juan Antonio Marchal 2 María Isabel Núñez 1 
  • PMID: 32660072
  •     259 References
  •     6 citations


Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial-mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

Keywords: CSC intratumoral radiosensitivity heterogeneity; CSC metabolism; CSC niche; accelerated repopulation; radiation resistance; signaling pathways; tumor microenvironment.

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Cancer Res, 2019 Nov 27; 80(2). PMID: 31767626
The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells.
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Int J Cancer, 2009 May 12; 125(3). PMID: 19431142
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Cancer stem cells and radiotherapy.
Michael Baumann, Mechthild Krause, +2 authors, Daniel Zips.
Int J Radiat Biol, 2009 Apr 22; 85(5). PMID: 19382020
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Sci Rep, 2015 Nov 26; 5. PMID: 26596243    Free PMC article.
The double edge sword of fibrosis in cancer.
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Microenvironmental Signals and Biochemical Information Processing: Cooperative Determinants of Intratumoral Plasticity and Heterogeneity.
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Nat Cell Biol, 2010 Apr 27; 12(5). PMID: 20418870
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Radiotherapy induces responses of lung cancer to CTLA-4 blockade.
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Nat Med, 2018 Nov 07; 24(12). PMID: 30397353    Free PMC article.
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Lin Yang, Guanghai Yang, +5 authors, Guangyuan Hu.
J Cancer, 2018 Mar 28; 9(5). PMID: 29581767    Free PMC article.
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Radiation resistance of cancer stem cells: the 4 R's of radiobiology revisited.
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Stem Cells, 2010 Feb 06; 28(4). PMID: 20135685    Free PMC article.
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Tumour heterogeneity and the evolutionary trade-offs of cancer.
Jean Hausser, Uri Alon.
Nat Rev Cancer, 2020 Feb 26; 20(4). PMID: 32094544
Increased Oxidative Stress as a Selective Anticancer Therapy.
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Cancer Res, 2007 May 08; 67(9). PMID: 17483312
Mesenchymal stem cell's secretome promotes selective enrichment of cancer stem-like cells with specific cytogenetic profile.
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Boron neutron capture therapy (BNCT) as a new approach for clear cell sarcoma (CCS) treatment: Trial using a lung metastasis model of CCS.
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Cancer Biol Ther, 2012 Feb 18; 13(1). PMID: 22336584
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Stem cells in breast tumours: are they ready for the clinic?
Matthew P Ablett, Jagdeep K Singh, Robert B Clarke.
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Apoptosis: A Target for Anticancer Therapy.
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Int J Mol Sci, 2018 Feb 03; 19(2). PMID: 29393886    Free PMC article.
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Antioxidant Mechanisms and ROS-Related MicroRNAs in Cancer Stem Cells.
Ilaria Dando, Marco Cordani, +3 authors, Marta Palmieri.
Oxid Med Cell Longev, 2015 Jun 13; 2015. PMID: 26064420    Free PMC article.
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Cancer Biol Med, 2017 Jun 14; 14(2). PMID: 28607802    Free PMC article.
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Cell Stem Cell, 2013 Sep 17; 13(5). PMID: 24035355
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Cancer stem cells and signaling pathways in radioresistance.
Lei Chang, Peter Graham, +6 authors, Yong Li.
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Exosomes, metastases, and the miracle of cancer stem cell markers.
Zhe Wang, Margot Zöller.
Cancer Metastasis Rev, 2019 Apr 29; 38(1-2). PMID: 31030373
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Semin Cancer Biol, 2014 Jun 24; 31. PMID: 24956577
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N Engl J Med, 2018 Oct 04; 379(24). PMID: 30280658
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The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines.
Geoff Delaney, Susannah Jacob, Carolyn Featherstone, Michael Barton.
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Naoko Takebe, Lucio Miele, +5 authors, S Percy Ivy.
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The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer.
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J Thorac Oncol, 2010 Nov 26; 6(1). PMID: 21107292
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Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics.
Rayana L Bighetti-Trevisan, Lucas O Sousa, Rogerio M Castilho, Luciana O Almeida.
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Nat Rev Cancer, 2008 Feb 08; 8(3). PMID: 18256616
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Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance.
Katrien Konings, Charlot Vandevoorde, +2 authors, Marjan Moreels.
Front Oncol, 2020 Mar 03; 10. PMID: 32117774    Free PMC article.
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MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.
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Cell Metab, 2015 Sep 15; 22(4). PMID: 26365176
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Establishment of animal model for the analysis of cancer cell metastasis during radiotherapy.
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Radiat Oncol, 2012 Sep 12; 7. PMID: 22963683    Free PMC article.
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J Thorac Oncol, 2007 Oct 03; 2(10). PMID: 17909354
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Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas.
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The phenotypic radiation resistance of CD44+/CD24(-or low) breast cancer cells is mediated through the enhanced activation of ATM signaling.
Hong Yin, Jonathan Glass.
PLoS One, 2011 Sep 22; 6(9). PMID: 21935375    Free PMC article.
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Cancer stem cells: A review from origin to therapeutic implications.
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Cancer stem cells: The potential of carbon ion beam radiation and new radiosensitizers (Review).
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Role of Microenvironment on the Fate of Disseminating Cancer Stem Cells.
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Front Oncol, 2019 Mar 09; 9. PMID: 30847298    Free PMC article.
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Int J Radiat Oncol Biol Phys, 2011 Jul 13; 82(5). PMID: 21745719
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Trends Cancer, 2017 Jul 26; 2(11). PMID: 28741502
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Cell Stem Cell, 2015 Mar 10; 16(3). PMID: 25748930    Free PMC article.
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Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers.
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Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status.
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Cancer stem cells and radiotherapy: new insights into tumor radioresistance.
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