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The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2.
Berg, Tracy J; Marques, Carolina; Pantazopoulou, Vasiliki; Johansson, Elinn; von Stedingk, Kristoffer; Lindgren, David; Jeannot, Pauline; Pietras, Elin J; Bergström, Tobias; Swartling, Fredrik J; Governa, Valeria; Bengzon, Johan; Belting, Mattias; Axelson, Håkan; Squatrito, Massimo; Pietras, Alexander.
Afiliación
  • Berg TJ; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Marques C; Seve Ballesteros Foundation Brain Tumor group, CNIO, Madrid, Spain.
  • Pantazopoulou V; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Johansson E; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • von Stedingk K; Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
  • Lindgren D; Department of Oncogenomics, M1-131 Academic Medical Center University of Amsterdam, Amsterdam, the Netherlands.
  • Jeannot P; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Pietras EJ; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Bergström T; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • Swartling FJ; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Governa V; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Bengzon J; Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
  • Belting M; Division of Neurosurgery, Department of Clinical Sciences, Lund Stem Cell Center, Lund University, Lund, Sweden.
  • Axelson H; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Squatrito M; Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
  • Pietras A; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Cancer Res ; 81(8): 2101-2115, 2021 04 15.
Article en En | MEDLINE | ID: mdl-33483373
The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. SIGNIFICANCE: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2101/F1.large.jpg.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Encéfalo / Neoplasias Encefálicas / Transglutaminasas / Astrocitos / Glioblastoma / Proteínas de Unión al GTP / Microambiente Tumoral Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Cancer Res Año: 2021 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Encéfalo / Neoplasias Encefálicas / Transglutaminasas / Astrocitos / Glioblastoma / Proteínas de Unión al GTP / Microambiente Tumoral Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Cancer Res Año: 2021 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos