TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

Pigeon, Hayet; Pérès, Elodie A.; Truillet, Charles; Jego, Benoît; Boumezbeur, Fawzi; Caillé, Fabien; Zinnhardt, Bastian; Jacobs, Andréas H.; Bihan, Denis Le; Winkeler, Alexandra

doi:10.1093/neuonc/noz029

Cited by 29 publications

(30 citation statements)

References 40 publications

(22 reference statements)

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“…We and others showed that [ 18 F]DPA-714 supports the identification of unique TSPO-expressing regions of the TME 20 , 22 that may represent areas with immunosuppressive myeloid cells 23 and glioma infiltration 24 , 54 . In spite of these promising results, very few studies describe the suitability of TSPO-binding radioligands for the monitoring of therapy outcomes 55 , 56 and even fewer specific for [ 18 F]DPA-714 in glioma.…”

Section: Discussionmentioning

confidence: 79%

“…Recent studies of TSPO-PET in conjunction with in-depth immunophenotyping suggested [ 18 F]DPA-714 to non-invasively image the degree and heterogeneity of the glioma-associated immunosuppressive tumor microenvironment (TME) in vivo 22 , 23 . In addition, [ 18 F]DPA-714 may reveal distinct areas of glioma activity 22 , 23 compared to other imaging biomarkers and may be superior over [ 18 F]FET in detection of glioma infiltration 24 .…”

Section: Introductionmentioning

confidence: 99%

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Imaging temozolomide-induced changes in the myeloid glioma microenvironment

et al. 2021

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Imaging temozolomide-induced changes in the myeloid glioma microenvironment

et al. 2021

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“…Additionally, in almost all types of CNS pathologies, TSPO levels are increased, and in some psychiatric disorders, such as schizophrenia, the TSPO signal in PET is decreased [34]. Although TSPO ligands are widely used in molecular imaging in all sorts of CNS pathologies, little is known about the role of TSPO expression and neuroinflammation in glioblastoma patients and PET imaging with TSPO radioligands is not yet standard for the imaging of brain tumor patients [18,19,[35][36][37]. In this study, we could show that the expression of TSPO is higher in brain tumor samples compared to those from epilepsy patients.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Cai

Kirchleitner

Zhao

et al. 2020

IJMS

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Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment.

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“…Despite its presence has been described also in tumors, increased levels of TSPO are associated with the presence of clusters of microglial/macrophage cells with an activated phenotype (23). For this reason, TSPO ligands, including [ 18 F]VC701 are used to image the inflammatory reaction present during tumor development and the relative modulation induced by drugs (24,25). Finally, to investigate therapy effects on tumor proliferation and inflammation markers, Ki67 and Iba1 were evaluated post mortem by immunohistochemistry (IHC).…”

Section: Introductionmentioning

confidence: 99%

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

et al. 2021

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Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [18F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [18F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro, MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival (bcl2) and pro-apoptotic (bax/bad) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo, MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [18F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [18F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals’ survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects.

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TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

Abstract: TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

Cited by 29 publications

References 40 publications

Imaging temozolomide-induced changes in the myeloid glioma microenvironment

Imaging temozolomide-induced changes in the myeloid glioma microenvironment

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

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