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Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2017 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 131, no 1, p. 83-92Article in journal (Refereed) Published
Abstract [en]

The knowledge of response to radiation in the immuno-microenvironment of high grade gliomas is sparse. In vitro results have indicated an inflammatory response of myeloid cells after irradiation. Therefore, microdialysis was used to verify whether this is operative in tumor tissue and brain adjacent to tumor (BAT) after clinical radiotherapy of patients with high grade glioma. Stereotactic biopsies and implantation of microdialysis catheters in tumor tissue and BAT were performed in eleven patients with high-grade glioma. The patients were given daily radiation fractions of 2-3.4 Gy. Microdialysis samples were collected before radiotherapy and during the first five days of radiation. Cytokines, glucose metabolites, glutamate and glycerol were analyzed. Immunohistochemistry was performed to detect macrophages (CD68) and monocytes (CD163) as well as IL-6, IL-8 and MCP-1. A significant increase of IL-8, MCP-1 and MIP-1a were detected in tumor tissue already after the first dose of radiation and increased further during 5 days of radiation. IL-6 did also increase but after five fractions of radiation. In BAT, the cytokine response was modest with significant increase of IL-8 after third dose of radiation. We found a positive correlation between baseline IL-8 and IL-6 microdialysis levels in tumor tissue and survival. Glucose metabolites or glycerol and glutamate did not change during radiation. In all tumors staining for macrophages was demonstrated. IL-6 was found in viable tumor cells while MCP-1 was demonstrated in macrophages or tumor matrix. Our findings suggest that radiation induces a rapid enhancement of the prevailing inflammation in high-grade glioma tissue. The microdialysis technique is feasible for this type of study and could be used to monitor metabolic changes after different interventions.

Place, publisher, year, edition, pages
Springer, 2017. Vol. 131, no 1, p. 83-92
Keywords [en]
Cytokine, Glioblastoma, Radiotherapy, Microdialysis, Inflammation
National Category
Cancer and Oncology Neurology
Identifiers
URN: urn:nbn:se:umu:diva-131132DOI: 10.1007/s11060-016-2271-1ISI: 000393065400010PubMedID: 27664151Scopus ID: 2-s2.0-84988693211OAI: oai:DiVA.org:umu-131132DiVA, id: diva2:1071794
Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2023-03-23Bibliographically approved
In thesis
1. Stereotactic microdialysis for metabolic assessment and experimental treatment of malignant glioma
Open this publication in new window or tab >>Stereotactic microdialysis for metabolic assessment and experimental treatment of malignant glioma
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glioblastoma multiforme, the most common primary brain tumor, has a dire prognosis despite multimodal treatments that include surgery and radio-chemotherapy. To improve the outcome of this destructive disease, we need to improve our understanding of its tumor biology. Furthermore, the development of new treatment strategies will improve with a better understanding of the interplay between malignant cells and their direct surrounding microenvironment.

This thesis aims to increase the understanding of the processes within high-grade glioma and its microenvironment during normal conditions as well as during the distress associated with treatment. Specifically, we have investigated the metabolic response to radiotherapy (study I and II), the immunologic response to radiotherapy (study II), and the metabolic response pattern to loco-regional treatment with cisplatin (study III and IV). Using microdialysis, we collected samples from the extracellular space in both normal brain and tumor tissue during radiotherapy (study I and II) and loco-regional cisplatin treatment (study III and IV). Theses samples were analyzed for glucose metabolites, glycerol, and glutamate (study I, II, and III) and for cytokines (study II). In addition, we analyzed the global metabolism with mass spectrometry to identify and assess the response pattern of malignant glioma cells to loco-regional cisplatin treatment (study IV).

In study I and II, we found that malignant glioma cells used glucose at a higher rate than normal cells and preferred glycolysis for glucose metabolism. The given radiation dose (2 Gray (Gy) daily for five days) did not significantly affect glucose metabolism, glycerol levels, or glutamate levels in tumor tissue or the microenvironment. However, in study II, we observed an induced inflammatory effect due to the given radiation dose as several of the cytokines investigated showed significantly increased levels during radiotherapy. In study IV, we observed a complex and strong metabolic response to the loco-regional cisplatin therapy. At baseline, we found a metabolic pattern corresponding well with highly proliferating tumor tissue–i.e., high levels of amino acids, their metabolites, and other metabolic end products and low levels of sugar derivatives, antioxidants, and nucleotides. During the loco-regional therapy, we observed a clearly localized cytotoxic effect within the tumor and a metabolic response pattern corresponding with cisplatin’s complex mechanism of action, affecting several metabolic pathways within the malignant cell. Glutamate and glycerol also increased in tumor tissue following loco-regional treatment, a finding that further supported the observation of local toxicity.

In study III, we investigated microdialysis as a method to assess the microenvironment in high-grade glioma and as a method for drug delivery (retrograde microdialysis). All studies demonstrated the usefulness of microdialysis as a tool for in vivo real-time assessment of molecular events in malignant glioma tissue. Although the method is invasive, no complications related to the surgical procedure or assessment were noted. In study III, we also demonstrated that retrograde microdialysis is a feasible method for locally delivering clinically significant doses of drugs such as cisplatin to tumor tissue in the brain. However, in addition to having a cytotoxic effect on tumor cells, cisplatin may induce clinically significant edema.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2020. p. 71
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2104
Keywords
Brain microdialysis, Glioblastoma multiforme, Malignant glioma, Retrograde microdialysis, Glucose metabolism, Radiotherapy, Chemotherapy, Cytokine.
National Category
Other Clinical Medicine
Research subject
Neurosurgery
Identifiers
urn:nbn:se:umu:diva-176052 (URN)978-91-7855-402-7 (ISBN)978-91-7855-403-4 (ISBN)
Public defence
2020-11-20, Hörsal B, Unod T9, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Cancer SocietyRegion VästerbottenSwedish Research CouncilCancerforskningsfonden i Norrland
Available from: 2020-10-30 Created: 2020-10-19 Last updated: 2020-10-20Bibliographically approved

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Tabatabaei, PedramBergström, PerBrännström, ThomasBergenheim, A Tommy

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