Low-grade intestinal inflammation two decades after pelvic radiotherapyResearch in context
Sravani Devarakonda,
Annika Thorsell,
Per Hedenström,
Azar Rezapour,
Lisen Heden,
Sanghita Banerjee,
Malin E.V. Johansson,
George Birchenough,
Amelie Toft Morén,
Karin Gustavsson,
Viktor Skokic,
Victor L. Pettersson,
Fei Sjöberg,
Marie Kalm,
Mohammad Al Masri,
Michaela Ekh,
Henrik Fagman,
Mats Wolving,
Rosie Perkins,
Rodrigo A. Morales,
Francisca Castillo,
Eduardo J. Villablanca,
Ulf Yrlid,
Karin Bergmark,
Gunnar Steineck,
Cecilia Bull
Affiliations
Sravani Devarakonda
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Annika Thorsell
Proteomics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Per Hedenström
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
Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Lisen Heden
Pelvic Cancer Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden
Sanghita Banerjee
Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
Malin E.V. Johansson
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
George Birchenough
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Amelie Toft Morén
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Karin Gustavsson
Pelvic Cancer Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden
Viktor Skokic
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
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Fei Sjöberg
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
Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden
Mohammad Al Masri
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Michaela Ekh
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Henrik Fagman
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
Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden
Rosie Perkins
Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
Rodrigo A. Morales
Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
Francisca Castillo
Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
Eduardo J. Villablanca
Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
Ulf Yrlid
Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Karin Bergmark
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Gunnar Steineck
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Cecilia Bull
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Corresponding author. Department of Oncology at the Institute of Clinical Sciences, University of Gothenburg, Box 423, Gothenburg, Sweden.
Summary: 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).
