Abstract
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.
Highlights
For many types of cancer, cancer stem cells (CSCs) represent a subpopulation with specific surface markers and functional properties including self-renewal capacity, long-term repopulation potential, Cells 2020, 9, 1651; doi:10.3390/cells9071651 www.mdpi.com/journal/cellsCells 2020, 9, 1651 and tumor initiation and progression capacity, which make these cells different from the bulk tumor cells [1,2].Tumor heterogeneity is responsible for the differing sensitivities of tumor cells to cancer treatment including radiotherapy (RT), which explains why tumor subpopulations are not affected by this treatment
Since the present work deals with CSC radioresistance, we review the main characteristics of this subpopulation, its plasticity and tumor heterogeneity associated with the number of CSCs within the tumor
matrix metalloproteases (MMPs) are essential for extracellular matrix (ECM) organization and tumor cells produce a series of soluble factors, cytokines, and chemokines that support the formation of the premetastatic niche through the recruitment of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg) [110]
Summary
For many types of cancer, cancer stem cells (CSCs) represent a subpopulation with specific surface markers and functional properties including self-renewal capacity, long-term repopulation potential, Cells 2020, 9, 1651; doi:10.3390/cells9071651 www.mdpi.com/journal/cells. The identification of molecular targets that control CSC can drive the development of new drugs able to eradicate and prevent the growth of new CSCs in patients This will help prevent metastasis and tumor relapse with a reduction of morbidity and toxicity, and improving the outcomes in cancer patients [19]. Thereby, this review offers insight into the mechanisms involved in CSC radioresistance and into the development of CSC-specific therapies combined with RT, some of which are being currently implemented in the clinical setting. This will allow a better understanding of the safety and efficacy of these combination therapies
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