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Effect of Fractionated Low-LET Radiation Exposure on Cervical Cancer Stem Cells under Experimental and Clinical Conditions

  • RADIOBIOLOGICAL BASES OF TUMOR RADIATION THERAPY
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Abstract—

Numerous studies have proven the high resistance of cancer stem cells (CSCs) to a single-dose low-LET ionizing radiation exposure in vitro. These data are the basis for the assumption about the important role of CSCs in cancer recurrence after conventional radiation therapy. However, the patterns and mechanisms of fractionated radiation effects on this population of cells have not been studied enough, and there are only a few publications regarding cervical cancer. Therefore, the purpose of this work is to elucidate the quantitative changes in the CSC population after low-LET radiation exposure using the conventional fractionation regimen in vitro (in cervical cancer cell lines HeLa and SiHa) and in vivo (in cervical scrapings from patients with squamous cell cervical cancer during radiation therapy). Using flow cytometry, the proportion of CSCs was measured in these cell lines after each dose fraction until a cumulative dose of 10 Gy was reached, and in clinical samples of 26 patients before treatment and after irradiation at a cumulative dose of 10 Gy to point A. CSCs were identified in cell cultures by the ability of these cells to pump out the fluorescent dye Hoechst 33 342 and form a side population (SP) and in cervical scrapings by the CD44+CD24low immunophenotype. A statistically significant increase in the proportion of CSCs was found after fractionated irradiation of cervical cell cultures in the range of 2–10 Gy, as compared with the nonirradiated control. High individual variability in the proportion of CD44+CD24low CSCs was detected in cervical scrapings before treatment and after radiation exposure. An irradiation-induced increase in this indicator was observed in 38% of patients; in other patients, a decrease in this indicator was found after irradiation at a cumulative dose of 10 Gy or its preservation at the initial level. A high inverse correlation was observed between the CSC proportion before treatment with its change after irradiation (R = –0.71; p < 0.0001). The results indicate significant individual differences in the response of cervical CSCs to radiation treatment and substantiate the fundamental possibility of further investigation of the prognostic significance of CSC quantitative changes after the first sessions of radiotherapy with regard to the short- and long-term results of treatment.

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Funding

The study of CSCs was supported by the Russian Science Foundation no. 18-75-10025. The diagnostics and treatment of the cervical patients were supported by the Medical Care Insurance Fund and a State Assignment of the Ministry of Health of the Russian Federation.

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Authors and Affiliations

  1. Tsyb Medical Radiological Research Center, Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia

    O. N. Matchuk, I. A. Zamulaeva, E. I. Selivanova, L. S. Mkrtchyan, L. I. Krikunova, V. O. Saburov, A. A. Lychagin, G. Z. Kuliyeva, A. O. Yakimova, A. V. Khokhlova, S. A. Ivanov & A. D. Kaprin

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  1. O. N. Matchuk
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  2. I. A. Zamulaeva
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  3. E. I. Selivanova
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  4. L. S. Mkrtchyan
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  5. L. I. Krikunova
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  6. V. O. Saburov
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  8. G. Z. Kuliyeva
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Correspondence to O. N. Matchuk.

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Statement of compliance with standards of research involving humans as subjects. This study was approved by the Ethics Committee of the Tsyb Medical Radiological Research Center (Obninsk, Russia). Informed consent was obtained from all individual participants involved in the study.

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Translated by M. Novikova

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Matchuk, O.N., Zamulaeva, I.A., Selivanova, E.I. et al. Effect of Fractionated Low-LET Radiation Exposure on Cervical Cancer Stem Cells under Experimental and Clinical Conditions. Biol Bull Russ Acad Sci 47, 1471–1479 (2020). https://doi.org/10.1134/S1062359020110096

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