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Low-grade intestinal inflammation two decades after pelvic radiotherapy

BACKGROUND: Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute...

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Autores principales: Devarakonda, Sravani, Thorsell, Annika, Hedenström, Per, Rezapour, Azar, Heden, Lisen, Banerjee, Sanghita, Johansson, Malin E.V., Birchenough, George, Toft Morén, Amelie, Gustavsson, Karin, Skokic, Viktor, Pettersson, Victor L., Sjöberg, Fei, Kalm, Marie, Al Masri, Mohammad, Ekh, Michaela, Fagman, Henrik, Wolving, Mats, Perkins, Rosie, Morales, Rodrigo A., Castillo, Francisca, Villablanca, Eduardo J., Yrlid, Ulf, Bergmark, Karin, Steineck, Gunnar, Bull, Cecilia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393618/
https://www.ncbi.nlm.nih.gov/pubmed/37480626
http://dx.doi.org/10.1016/j.ebiom.2023.104691
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author Devarakonda, Sravani
Thorsell, Annika
Hedenström, Per
Rezapour, Azar
Heden, Lisen
Banerjee, Sanghita
Johansson, Malin E.V.
Birchenough, George
Toft Morén, Amelie
Gustavsson, Karin
Skokic, Viktor
Pettersson, Victor L.
Sjöberg, Fei
Kalm, Marie
Al Masri, Mohammad
Ekh, Michaela
Fagman, Henrik
Wolving, Mats
Perkins, Rosie
Morales, Rodrigo A.
Castillo, Francisca
Villablanca, Eduardo J.
Yrlid, Ulf
Bergmark, Karin
Steineck, Gunnar
Bull, Cecilia
author_facet Devarakonda, Sravani
Thorsell, Annika
Hedenström, Per
Rezapour, Azar
Heden, Lisen
Banerjee, Sanghita
Johansson, Malin E.V.
Birchenough, George
Toft Morén, Amelie
Gustavsson, Karin
Skokic, Viktor
Pettersson, Victor L.
Sjöberg, Fei
Kalm, Marie
Al Masri, Mohammad
Ekh, Michaela
Fagman, Henrik
Wolving, Mats
Perkins, Rosie
Morales, Rodrigo A.
Castillo, Francisca
Villablanca, Eduardo J.
Yrlid, Ulf
Bergmark, Karin
Steineck, Gunnar
Bull, Cecilia
author_sort Devarakonda, Sravani
collection PubMed
description BACKGROUND: Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors. METHODS: We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection. FINDINGS: 942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration. INTERPRETATION: Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors. FUNDING: This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow’s foundation (MA and VP).
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spelling pubmed-103936182023-08-03 Low-grade intestinal inflammation two decades after pelvic radiotherapy Devarakonda, Sravani Thorsell, Annika Hedenström, Per Rezapour, Azar Heden, Lisen Banerjee, Sanghita Johansson, Malin E.V. Birchenough, George Toft Morén, Amelie Gustavsson, Karin Skokic, Viktor Pettersson, Victor L. Sjöberg, Fei Kalm, Marie Al Masri, Mohammad Ekh, Michaela Fagman, Henrik Wolving, Mats Perkins, Rosie Morales, Rodrigo A. Castillo, Francisca Villablanca, Eduardo J. Yrlid, Ulf Bergmark, Karin Steineck, Gunnar Bull, Cecilia eBioMedicine Articles BACKGROUND: Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors. METHODS: We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection. FINDINGS: 942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration. INTERPRETATION: Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors. FUNDING: This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow’s foundation (MA and VP). Elsevier 2023-07-20 /pmc/articles/PMC10393618/ /pubmed/37480626 http://dx.doi.org/10.1016/j.ebiom.2023.104691 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Articles
Devarakonda, Sravani
Thorsell, Annika
Hedenström, Per
Rezapour, Azar
Heden, Lisen
Banerjee, Sanghita
Johansson, Malin E.V.
Birchenough, George
Toft Morén, Amelie
Gustavsson, Karin
Skokic, Viktor
Pettersson, Victor L.
Sjöberg, Fei
Kalm, Marie
Al Masri, Mohammad
Ekh, Michaela
Fagman, Henrik
Wolving, Mats
Perkins, Rosie
Morales, Rodrigo A.
Castillo, Francisca
Villablanca, Eduardo J.
Yrlid, Ulf
Bergmark, Karin
Steineck, Gunnar
Bull, Cecilia
Low-grade intestinal inflammation two decades after pelvic radiotherapy
title Low-grade intestinal inflammation two decades after pelvic radiotherapy
title_full Low-grade intestinal inflammation two decades after pelvic radiotherapy
title_fullStr Low-grade intestinal inflammation two decades after pelvic radiotherapy
title_full_unstemmed Low-grade intestinal inflammation two decades after pelvic radiotherapy
title_short Low-grade intestinal inflammation two decades after pelvic radiotherapy
title_sort low-grade intestinal inflammation two decades after pelvic radiotherapy
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393618/
https://www.ncbi.nlm.nih.gov/pubmed/37480626
http://dx.doi.org/10.1016/j.ebiom.2023.104691
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