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Epidermal Keratinocyte Depletion during Five Weeks of Radiotherapy is Associated with DNA Double-Strand Break Foci, Cell Growth Arrest and Apoptosis: Evidence of Increasing Radioresponsiveness and Lack of Repopulation; the Number of Melanocytes Remains Unchanged.
Radiation Research ( IF 2.5 ) Pub Date : 2020-03-20 , DOI: 10.1667/rr15417.1
Ingela Turesson 1 , Martin Simonsson 1 , Ingegerd Hermansson 2 , Majlis Book 1 , Sunna Sigurdadottir 1 , Ulf Thunberg 1 , Fredrik Qvarnström 1 , Karl-Axel Johansson 3 , Per Fessé 4 , Jan Nyman 2
Affiliation  

During fractionated radiotherapy, epithelial cell populations are thought to decrease initially, followed by accelerated repopulation to compensate cell loss. However, previous findings in skin with daily 1.1 Gy dose fractions indicate continued and increasing cell depletion. Here we investigated epidermal keratinocyte response with daily 2 Gy fractions as well as accelerated and hypofractionation. Epidermal interfollicular melanocytes were also assessed. Skin-punch biopsies were collected from breast cancer patients before, during and after mastectomy radiotherapy to the thoracic wall with daily 2 Gy fractions for 5 weeks. In addition, 2.4 Gy radiotherapy four times per week and 4 Gy fractions twice per week for 5 weeks, and two times 2 Gy daily for 2.5 weeks, were used. Basal keratinocyte density of the interfollicular epidermis was determined and immunostainings of keratinocytes for DNA double-strand break (DSB) foci, growth arrest, apoptosis and mitosis were quantified. In addition, interfollicular melanocytes were counted. Initially minimal keratinocyte loss was observed followed by pronounced depletion during the second half of treatment and full recovery at 2 weeks post treatment. DSB foci per cell peaked towards the end of treatment. p21-stained cell counts increased during radiotherapy, especially the second half. Apoptotic frequency was low throughout radiotherapy but increased at treatment end. Mitotic cell count was significantly suppressed throughout radiotherapy and did not recover during weekend treatment gaps, but increased more than threefold compared to unexposed skin 2 weeks post-radiotherapy. The number of melanocytes remained constant over the study period. Germinal keratinocyte loss rate increased gradually during daily 2 Gy fractions for 5 weeks, and similarly for hypofractionation. DSB foci number after 2 Gy irradiation revealed an initial radioresistance followed by increasing radiosensitivity. Growth arrest mediated by p21 strongly suggests that cells within or recruited into the cell cycle during treatment are at high risk of loss and do not contribute significantly to repopulation. It is possible that quiescent (G0) cells at treatment completion accounted for the accelerated post-treatment repopulation. Recent knowledge of epidermal tissue regeneration and cell cycle progression during genotoxic and mitogen stress allows for a credible explanation of the current finding. Melanocytes were radioresistant regarding cell depletion.

中文翻译:

放射治疗五周期间表皮角质形成细胞的减少与DNA双链断裂灶,细胞生长受阻和凋亡有关:放射反应性增强和缺乏种群的证据。黑色素细胞的数量保持不变。

在分级放疗过程中,上皮细胞数量最初被认为减少,随后加速了种群的增长以补偿细胞的损失。但是,以前每天以1.1 Gy剂量剂量在皮肤中发现的结果表明,细胞消耗持续增加。在这里,我们调查了每日2 Gy分数以及加速和超分割后的表皮角质形成细胞反应。还评估了表皮小泡间黑色素细胞。在乳房切除术放疗之前,期间和之后,从乳腺癌患者中收集皮肤穿刺活组织检查,每天2 Gy分数,持续5周。此外,每周两次使用2.4 Gy放射疗法,每周两次两次进行4 Gy放射治疗,持续5周,每天两次两次,每次2 Gy放射治疗,持续2.5周。测定小泡间表皮的基础角质形成细胞密度,并对角质形成细胞的DNA双链断裂(DSB)灶,生长停滞,凋亡和有丝分裂进行免疫染色。另外,计数小泡间黑素细胞。最初观察到最小的角质形成细胞损失,随后在治疗的后半段明显耗竭,并在治疗后2周完全恢复。每个细胞的DSB病灶在治疗结束时达到峰值。在放疗期间,尤其是下半年,p21染色的细胞计数增加。在整个放疗过程中,细胞凋亡的频率均较低,但在治疗结束时细胞凋亡频率增加。在放疗期间,有丝分裂细胞的数量被显着抑制,并且在周末的治疗间隙中没有恢复,但是与放疗后2周未暴露的皮肤相比,有丝分裂细胞的数量增加了三倍以上。在研究期间,黑素细胞的数量保持不变。在每天2 Gy的分数持续5周期间,生殖器角质形成细胞的丢失率逐渐增加,而对于次分割也是如此。2 Gy照射后,DSB病灶数显示出最初的放射抗性,随后放射敏感性增加。由p21介导的生长停滞强烈表明在治疗期间处于细胞周期内或募集到细胞周期中的细胞处于高丢失风险中,并且对重新种群没有明显贡献。处理完成时的静态(G0)细胞可能是导致治疗后重新聚集的原因。表皮组织再生和基因毒性和有丝分裂原应激过程中细胞周期进程的最新知识为当前的发现提供了可靠的解释。黑色素细胞在细胞耗竭方面具有放射抗性。
更新日期:2020-03-20
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