Kimberly M Arnold1,2, Lynn M Opdenaker1,3, Nicole J Flynn1,3, Daniel Kwesi Appeah1,3, Jennifer Sims-Mourtada1,3. 1. Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Christiana Care Health Services, Inc, Newark, DE, USA. 2. Department of Medical Laboratory Sciences, The University of Delaware, Newark, DE, USA. 3. Department of Biological Sciences, The University of Delaware, Newark, DE, USA.
Abstract
Purpose: 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 nonstem cells. However, the role of IL-6/STAT3 in radiation-induced changes in cellular plasticity is unclear.Materials and methods: 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 nonstem cell populations, experiments were also carried out in ALDEFLUOR sorted cells. Results: 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 reprograming. However, inhibition of STAT3 blocked the radiation-induced stem-like state in both ALDEFLUOR positive and negative populations, and enhanced radiosensitivity.Conclusions: Radiation-induced changes in cellular plasticity are STAT3 dependent and may be a potential target to reduce radioresistance in TNBC and improve treatment outcome.
Purpose: 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 nonstem cells. However, the role of IL-6/STAT3 in radiation-induced changes in cellular plasticity is unclear.Materials and methods: 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 nonstem cell populations, experiments were also carried out in ALDEFLUOR sorted cells. Results: 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 reprograming. However, inhibition of STAT3 blocked the radiation-induced stem-like state in both ALDEFLUOR positive and negative populations, and enhanced radiosensitivity.Conclusions: Radiation-induced changes in cellular plasticity are STAT3 dependent and may be a potential target to reduce radioresistance in TNBC and improve treatment outcome.
Authors: Ina H Benoy; Roberto Salgado; Peter Van Dam; Katrien Geboers; Eric Van Marck; Simon Scharpé; Peter B Vermeulen; Luc Y Dirix Journal: Clin Cancer Res Date: 2004-11-01 Impact factor: 12.531
Authors: Wei Wei; David J Tweardy; Mei Zhang; Xiaomei Zhang; John Landua; Ivana Petrovic; Wen Bu; Kevin Roarty; Susan G Hilsenbeck; Jeffrey M Rosen; Michael T Lewis Journal: Stem Cells Date: 2014-10 Impact factor: 6.277
Authors: Kimberly M Arnold; Nicole J Flynn; Adam Raben; Lindsay Romak; Yan Yu; Adam P Dicker; Firas Mourtada; Jennifer Sims-Mourtada Journal: Cancer Growth Metastasis Date: 2018-03-09
Authors: Nicole J Toney; Lynn M Opdenaker; Kader Cicek; Lisa Frerichs; Christopher Ryan Kennington; Samuel Oberly; Holly Archinal; Rajasekharan Somasundaram; Jennifer Sims-Mourtada Journal: J Transl Med Date: 2022-03-07 Impact factor: 5.531