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Title: Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

Abstract

Purpose: To establish and characterize radiation-induced esophagitis (RIE) in vivo and in vitro. Methods and Materials: Fractionated thoracic irradiation at 0, 8, 12, or 15 Gy was given daily for 5 days to Balb/c or C57Bl/6 mice. Changes in body weight gain and daily food intake were assessed. At the end of the study, we removed the esophagus and examined histology by hematoxylin and eosin staining, immune cell infiltration and apoptosis by fluorescence-activated cell sorting, and gene expression changes by quantitative real-time polymerase chain reaction. Het-1A human esophageal epithelial cells were irradiated at 6 Gy, treated with recombinant human growth factors, and examined for gene expression changes, apoptosis, proliferation, and signal transduction pathways. Results: We observed that irradiation at 12 Gy or 15 Gy per fraction produced significant reduction in body weight and decreased food intake in Balb/c mice but not as much in C57Bl/6 mice. Further analyses of Balb/c mice irradiated at 12 Gy/fraction revealed attenuated epithelium, inflamed mucosa, and increased numbers of infiltrating CD4+ helper T cells and apoptotic cells. Moreover, we found that expression of tissue inhibitor for metalloproteinase-1, plasminogen activator inhibitor-1, granulocyte macrophage-colony stimulating factor, vascular endothelial growth factor, and stromal-derived factor-1 were increased, whereas epidermal growth factor (EGF) was decreased. Irradiated Het-1A cells similarlymore » showed a significant decrease in expression of EGF and connective tissue growth factor (CTGF). Treatment of EGF but not CTGF partially protected Het-1A cells from radiation-induced apoptosis and revealed phosphorylation of EGFR, AKT, and ERK signaling pathways. Conclusions: We established a mouse model of RIE in Balb/c mice with 12 Gy × 5 fractions, which showed reduced body weight gain, food intake, and histopathologic features similar to those of human esophagitis. Decreased EGF expression in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.« less

Authors:
 [1]; ; ; ; ; ;  [2];  [2];  [1]
  1. Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)
  2. Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of)
Publication Date:
OSTI Identifier:
22648717
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 95; Journal Issue: 3; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; CELL PROLIFERATION; CONNECTIVE TISSUE; ESOPHAGUS; FLUORINE COMPOUNDS; FOOD; FRACTIONATED IRRADIATION; GROWTH FACTORS; GY RANGE 01-10; GY RANGE 10-100; IN VITRO; IN VIVO; INTAKE; MICE; MUCOUS MEMBRANES; POLYMERASE CHAIN REACTION; RADIOTHERAPY

Citation Formats

Kim, Kyung Su, Jeon, Seong-Uk, Lee, Chan-Ju, Kim, Young-Eun, Bok, Seoyeon, Hong, Beom-Ju, Park, Dong-Young, Ahn, G-One, E-mail: goneahn@postech.ac.kr, and Kim, Hak Jae, E-mail: khjae@snu.ac.kr. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.02.051.
Kim, Kyung Su, Jeon, Seong-Uk, Lee, Chan-Ju, Kim, Young-Eun, Bok, Seoyeon, Hong, Beom-Ju, Park, Dong-Young, Ahn, G-One, E-mail: goneahn@postech.ac.kr, & Kim, Hak Jae, E-mail: khjae@snu.ac.kr. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy. United States. doi:10.1016/J.IJROBP.2016.02.051.
Kim, Kyung Su, Jeon, Seong-Uk, Lee, Chan-Ju, Kim, Young-Eun, Bok, Seoyeon, Hong, Beom-Ju, Park, Dong-Young, Ahn, G-One, E-mail: goneahn@postech.ac.kr, and Kim, Hak Jae, E-mail: khjae@snu.ac.kr. 2016. "Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy". United States. doi:10.1016/J.IJROBP.2016.02.051.
@article{osti_22648717,
title = {Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy},
author = {Kim, Kyung Su and Jeon, Seong-Uk and Lee, Chan-Ju and Kim, Young-Eun and Bok, Seoyeon and Hong, Beom-Ju and Park, Dong-Young and Ahn, G-One, E-mail: goneahn@postech.ac.kr and Kim, Hak Jae, E-mail: khjae@snu.ac.kr},
abstractNote = {Purpose: To establish and characterize radiation-induced esophagitis (RIE) in vivo and in vitro. Methods and Materials: Fractionated thoracic irradiation at 0, 8, 12, or 15 Gy was given daily for 5 days to Balb/c or C57Bl/6 mice. Changes in body weight gain and daily food intake were assessed. At the end of the study, we removed the esophagus and examined histology by hematoxylin and eosin staining, immune cell infiltration and apoptosis by fluorescence-activated cell sorting, and gene expression changes by quantitative real-time polymerase chain reaction. Het-1A human esophageal epithelial cells were irradiated at 6 Gy, treated with recombinant human growth factors, and examined for gene expression changes, apoptosis, proliferation, and signal transduction pathways. Results: We observed that irradiation at 12 Gy or 15 Gy per fraction produced significant reduction in body weight and decreased food intake in Balb/c mice but not as much in C57Bl/6 mice. Further analyses of Balb/c mice irradiated at 12 Gy/fraction revealed attenuated epithelium, inflamed mucosa, and increased numbers of infiltrating CD4+ helper T cells and apoptotic cells. Moreover, we found that expression of tissue inhibitor for metalloproteinase-1, plasminogen activator inhibitor-1, granulocyte macrophage-colony stimulating factor, vascular endothelial growth factor, and stromal-derived factor-1 were increased, whereas epidermal growth factor (EGF) was decreased. Irradiated Het-1A cells similarly showed a significant decrease in expression of EGF and connective tissue growth factor (CTGF). Treatment of EGF but not CTGF partially protected Het-1A cells from radiation-induced apoptosis and revealed phosphorylation of EGFR, AKT, and ERK signaling pathways. Conclusions: We established a mouse model of RIE in Balb/c mice with 12 Gy × 5 fractions, which showed reduced body weight gain, food intake, and histopathologic features similar to those of human esophagitis. Decreased EGF expression in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.},
doi = {10.1016/J.IJROBP.2016.02.051},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 95,
place = {United States},
year = 2016,
month = 7
}
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  • In an effort to identify events initiating up-regulation of epidermal growth factor receptor after single and repeated radiation exposures, we investigated the role of epidermal growth factor receptor, a receptor protein tyrosine kinase, in radiation-induced signal transduction. Human malignant mammary, MCF-7, and squamous, A431, cells showed low baseline phospho-tyrosine levels of epidermal growth factor receptor, permitting reproducible dose-dependent stimulation of epidermal growth factor receptor autophosphorylation after exposure to epidermal growth factor. MCF-7 cells exhibited a mean 2.3-fold increase (95% confidence interval: 1.91, 2.65; P < 0.0001) in levels of epidermal growth factor phosphorylation in response to exposures of 2 Gy,more » which was substantially less than the epidermal growth factor receptor Y phosphorylation induced by epidermal growth factor. A quantitatively similar radiation response was seen in A431 cells. In the dose range of 1 to 4 Gy, no clear dose response was seen. There was a rapid induction of radiation-induced epidermal growth factor receptor Y phosphorylation, starting within 2 min, with maximum values between 0.5 and 5 min after radiation exposure followed by a slower decline to baseline levels after 20 min. The data presented identify the epidermal growth factor receptor protein tyrosine kinase associated with the plasma membrane as one target for ionizing radiation in the dose range used in radiotherapy. 20 refs., 4 figs.« less
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