Abstract
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.
Highlights
Glioblastoma (GBM) represents the majority of primary central nervous system (CNS) neoplasms in adults [1]
By the immunostaining of GBM patient samples, patient-derived xenografts, and murine genetic subtype models, we show that translocator protein (TSPO) expression is detected in tumor cells, as well as the tumor microenvironment, especially tumor-associated myeloid cells, pericytes, and endothelial cells, while LAT1 seems to be restricted to the tumor cells themselves
We found that high TSPO or AIF1 expression was associated with significantly shorter survival, while high SLC7A5 (=LAT1) levels were correlated with an increased survival (Figure 6B)
Summary
Glioblastoma (GBM) represents the majority of primary central nervous system (CNS) neoplasms in adults [1]. The TCGA glioblastoma dataset was analysed for the expression of TSPO and SLC7A5 (=LAT1), encoding for the molecular targets of TSPO- and FET-PET, and for AIF1, as we found a high TSPO level in microglia and macrophages By conducting this analysis, we found a significant increase in the gene expression of TSPO and AIF1 in GBM compared to that of healthy brain tissue (Figure 6A). We found that high TSPO or AIF1 expression was associated with significantly shorter survival, while high SLC7A5 (=LAT1) levels were correlated with an increased survival (Figure 6B) Based on this finding, we analysed an additional GBM cohort consisting of 12 patient samples by immunohistochemistry for TSPO- or Iba1-positive cells and quantified numbers
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