Molecular mechanisms underlying radioresistance: data compiled from isogenic cell experiments

Radiotherapy is an essential component of cancer therapy. Theoretically, a sufficiently high dose of radiation should achieve complete tumor control. However, in three-dimensional conformal radiotherapy (3D-CRT), which is a commonly used modality, the dose delivered to the tumor is often compromised to prevent adverse effects on normal tissues surrounding the tumor. Newer modalities such as intensity-modulated radiotherapy, stereotactic body radiotherapy, and particle radiotherapy can achieve higher dose conformality than 3D-CRT, leading to a higher dose delivery to the tumor. However, these high-precision radiotherapy modalities are less prevalent than 3D-CRT. Therefore, to maximize the efficacy of medical resources for radiotherapy as a whole, stratification of tumors based on photon sensitivity is crucial. This would lead to the preferential use of high-precision modalities for the treatment of relatively radioresistant tumors. To this end, the molecular mechanisms underlying cancer cell radioresistance need to be elucidated.

In a study published in January, 2020, in Annals of Translational Medicine (1), Zhou et al. performed fractionated X-ray irradiation of a breast cancer cell line, MDA-MB-231, and established a radioresistant subline as well as mouse xenografts. Comparison of gene expression profiles between the parental line and the radioresistant subline identified CDKN1A and SOD2 as upregulated genes in the radioresistant cells. The authors also demonstrated that high CDKN1A/SOD2 expression could predict a poor prognosis for breast cancer patients. These data provide insight into the response of breast cancer to radiotherapy. In addition, the models developed are a useful tool for further investigation into this issue.

Zhou et al. (1) demonstrated that the establishment and analysis of isogenic radioresistant sublines is a powerful strategy to explore the mechanisms underlying cancer cell radioresistance, which has been the subject of research for decades (Table 1). Previous studies suggested resistance to apoptosis (2,8-10,14,21,23) and high DNA repair capacity (7,9,13,19,23) as candidate mechanisms. In addition, studies show an association between radioresistance and high cellular migration (8,23,24) and antioxidant (1,9,17) capacities. Regarding the signaling pathways involved, the MAPK (18,22,24), PI3K (18,20,22,24), and JAK-STAT (12,22) axes consistently show increased activity in radioresistant cells. Activation of molecules associated with multi-drug resistance (9,25) and epithelial-mesenchymal transition (11), alterations of cell cycle profiles (1,23) and immune systems (16), and other mechanisms (3-6,15) have also been reported as possible mechanisms associated with radioresistance. These findings provide an important biological basis for understanding the mechanisms underlying radioresistance. However, there is considerable variation among studies in the establishment of radioresistant cell lines in terms of histology of the cell line and irradiation protocols (i.e., total dose, single dose, and irradiation interval) (Table 1). Cross-validation of the results is necessary in the future to build robust evidence that can be translated to the clinic.

Table 1 Summary of previous studies that established isogenic radioresistant human cancer cell lines
Full table

In summary, studies on isogenic radioresistant cell lines provide clues to understand the mechanisms underlying cancer cell radioresistance, which will facilitate personalization of radiotherapy.

Acknowledgments

Funding: This work was supported by Gunma University Heavy Ion Medical Center and by Grants-in-Aid from the Japan Society for the Promotion of Science for KAKENHI [19K17162].

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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