Radiation induces an inflammatory response that results in STAT3-dependent changes in cellular plasticity and radioresistance of breast cancer stem-like cells.
Radiation induces an inflammatory response that results in STAT3-dependent changes in cellular plasticity and radioresistance of breast cancer stem-like cells.
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DOI：
10.1080/09553002.2020.1705423
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发表时间：
2020-04
影响因子：
2.6
通讯作者：
Sims-Mourtada J
中科院分区：
文献类型：
--
作者：
Arnold KM;Opdenaker LM;Flynn NJ;Appeah DK;Sims-Mourtada J
肿瘤微环境中的促炎细胞因子（例如 IL-6）有助于维持干细胞并促进其在治疗后的存活。 IL-6/STAT3 通路是癌症进展相关基因的关键调节因子。 STAT3 的激活促进三阴性乳腺癌中癌症干细胞的扩增。辐射还被证明可以扩大癌症干细胞群，并可以诱导非干细胞的干细胞性。然而，IL-6/STAT3 在辐射诱导的细胞可塑性变化中的作用尚不清楚。通过实时PCR和ELISA测定放射治疗后三阴性乳腺癌细胞系SUM159PT和MDA-MB-231的IL-6的表达和分泌。通过蛋白质印迹法测定辐射后 STAT3 的激活。通过检查 ALDEFLUOR 活性、乙醛脱氢酶异构体的基因表达分析以及添加和不添加 STAT3 抑制剂的微球形成测定来确定辐射诱导的细胞可塑性的变化。为了确定辐射对非干细胞群的影响，还在 ALDEFLUOR 分选细胞中进行了实验。辐射在两种细胞系中诱导炎症反应，导致 STAT3 激活。此外，辐射诱导了茎样状态，ALDH 异构体 ALDH1A1 和 ALDH1A3 的活性和表达增加，以及自我更新能力增加证明了这一点。辐射增加了非干细胞 (ALDH−) 群体中的 ALDH 活性和自我更新，表明辐射诱导了细胞重编程。然而，抑制 STAT3 可以阻断 ALDEFLUOR 阳性和阴性群体中辐射诱导的茎样状态，并增强放射敏感性。辐射引起的细胞可塑性变化是 STAT3 依赖性的，可能是降低 TNBC 放射抗性和改善治疗结果的潜在目标。
Pro-inflammatory cytokines within the tumor microenvironment, such as IL-6, contribute to the maintenance of stem cells and promote their survival following treatment. The IL-6/STAT3 pathway is a key regulator of genes involved in cancer progression. Activation of STAT3 promotes expansion of cancer stem cells in triple negative breast cancer. Radiation has also been shown to expand cancer stem cell populations and can induce stemness in non-stem cells. However, the role of IL-6/STAT3 in radiation induced changes in cellular plasticity is unclear. Expression and secretion of IL-6 from triple negative breast cancer cell lines SUM159PT and MDA-MB-231 were determined after radiation treatment by real-time PCR and ELISA. Activation of STAT3 after radiation was determined by western blotting. Changes in cellular plasticity induced by radiation were determined by examining ALDEFLUOR activity, gene expression analysis of aldehyde dehydrogenase isoforms and mammosphere forming assays with and without the addition of STAT3 inhibitors. To determine the effect of radiation on non-stem cell populations, experiments were also carried out in ALDEFLUOR sorted cells. Radiation induced an inflammatory response in both cell lines that resulted in activation of STAT3. Additionally, radiation induced a stem-like state as evidenced by an increased activity and expression of the ALDH isoforms ALDH1A1 and ALDH1A3, and increased self-renewal capabilities. Radiation increased ALDH activity and self-renewal in non-stem cell (ALDH−) populations, suggesting radiation induced cellular reprogramming. However, inhibition of STAT3 blocked the radiation-induced stem-like state in both ALDEFLUOR positive and negative populations, and enhanced radiosensitivity. Radiation-induced changes in cellular plasticity are STAT3 dependent and may be a potential target to reduce radioresistance in TNBC and improve treatment outcome.
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影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
5.2
作者：
Chung SS;Giehl N;Wu Y;Vadgama JV
通讯作者：
Vadgama JV
影响因子：
10.5
作者：
Dang Vinh Do;Ueda, Jun;Fu, Xin-Yuan
通讯作者：
Fu, Xin-Yuan
影响因子：
6.4
作者：
Banerjee K;Resat H
通讯作者：
Resat H
影响因子：
11.5
作者：
Benoy, IH;Salgado, R;Dirix, LY
通讯作者：
Dirix, LY