Low-grade intestinal inflammation two decades after pelvic radiotherapy.

Neutrophil Pelvic radiation disease Pelvic radiotherapy Proctitis Proteomics Transcriptomics

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Aug 2023
Historique:
received: 06 03 2023
revised: 13 06 2023
accepted: 19 06 2023
pubmed: 23 7 2023
medline: 23 7 2023
entrez: 22 7 2023
Statut: ppublish

Résumé

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. 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. 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. 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. 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).

Sections du résumé

BACKGROUND 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 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 RESULTS
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 CONCLUSIONS
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 BACKGROUND
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).

Identifiants

DOI: 10.1016/j.ebiom.2023.104691 PMID: 37480626 PMC: PMC10393618
pubmed: 37480626
pii: S2352-3964(23)00256-6
doi: 10.1016/j.ebiom.2023.104691
pmc: PMC10393618
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104691

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M Kalm is an employee at AstraZeneca. The other authors have nothing to disclose.

Auteurs

Sravani Devarakonda (S)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Annika Thorsell (A)

Proteomics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Per Hedenström (P)

Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Azar Rezapour (A)

Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Lisen Heden (L)

Pelvic Cancer Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden.

Sanghita Banerjee (S)

Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.

Malin E V Johansson (MEV)

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

George Birchenough (G)

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Amelie Toft Morén (A)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Karin Gustavsson (K)

Pelvic Cancer Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden.

Viktor Skokic (V)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Molecular Medicine and Surgery and Department of Pelvic Cancer, Karolinska Institute, Stockholm, Sweden.

Victor L Pettersson (VL)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Fei Sjöberg (F)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden.

Marie Kalm (M)

Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden.

Mohammad Al Masri (M)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Michaela Ekh (M)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Henrik Fagman (H)

Department of Laboratory Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg and Department of Clinical Patology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Mats Wolving (M)

Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.

Rosie Perkins (R)

Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Rodrigo A Morales (RA)

Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.

Francisca Castillo (F)

Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.

Eduardo J Villablanca (EJ)

Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.

Ulf Yrlid (U)

Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Karin Bergmark (K)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Gunnar Steineck (G)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Cecilia Bull (C)

Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: Cecilia.bull@gu.se.

Classifications MeSH