Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells
Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells
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DOI：
10.3390/ijms21020612
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发表时间：
2020-01-02
影响因子：
5.6
通讯作者：
Kaelin, Roland E.
中科院分区：
文献类型：
--
作者：
Cai, Linzhi;Kirchleitner, Sabrina V.;Kaelin, Roland E.
分子影像学对胶质母细胞瘤患者的诊断和治疗计划至关重要。正电子发射断层扫描（PET）与示踪剂用于检测溶质载体家族7成员5（SLC 7A 5;也称为氨基酸转运蛋白轻链L系统，LAT 1）和线粒体转运蛋白（TSPO）被成功地用于提供额外的信息肿瘤体积和预后。目前用于TSPO-PET和通过LAT 1（FET-PET）的示踪剂（[18 F]氟乙基酪氨酸，FET）摄取的可视化的方法尚未利用这些分子成像技术的全部诊断潜力。因此，我们研究了TSPO和LAT 1在患者胶质母细胞瘤（GBM）样品中以及在代表不同遗传亚型的患者GBM的各种GBM小鼠模型中的表达。通过免疫组织化学，我们发现与正常脑组织相比，TSPO和LAT 1在人GBM样品中上调。接下来，我们原位植入患者来源的GBM细胞，以及基因工程改造的小鼠GBM细胞，代表该疾病的不同遗传亚型。为了确定TSPO和LAT 1的表达，我们进行了免疫荧光染色。我们发现，与邻近的小鼠脑组织相比，TSPO和LAT 1表达在植入的人或鼠GBM细胞的肿瘤区域中增加。虽然LAT 1主要局限于肿瘤细胞，但我们发现TSPO也表达于小胶质细胞、肿瘤相关巨噬细胞、内皮细胞和周细胞。癌症基因组图谱（TCGA）数据分析证实了与无肿瘤脑组织相比，在更大的GBM患者样本队列中TSPO的上调。此外，与对照组相比，AIF 1（编码骨髓细胞标记物Iba 1的基因）在GBM中也上调。有趣的是，TSPO以及AIF 1根据GBM遗传亚型显示出显著不同的表达水平，其中在间充质亚型中表现出最高的表达。与低表达相比，高TSPO和AIF 1表达也与患者生存率的显著降低相关。与该发现一致，与IDH突变体（IDHMUT）GBM相比，TSPO和AIFl的表达水平在（异柠檬酸脱氢酶野生型）IDHWT中也显著更高。另一方面，LAT 1表达在各个GBM亚型之间没有差异。因此，我们可以得出结论，FET-和TSPO-PET赋予不同的信息的病理特征的基础上不同的遗传GBM亚型，因此可能有助于规划个性化的策略，脑肿瘤治疗的未来。TSPO-PET和FET-PET的组合可能是一种有前途的方法，可以可视化肿瘤相关的骨髓细胞，并选择患者进行靶向骨髓室的治疗策略。
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.