gms | German Medical Science

Objective: Positron emission tomography (PET) with the amino acid analogue 18F-fluoro-ethyl-tyrosine (FET) has become extremely important for the diagnosis and therapy planning of glioma patients. New PET tracers against the translocator protein TSPO, which is overexpressed primarily by glioma cells and tumor-associated myeloid cells (TAM), are potentially of interest for diagnostics. The use of this new imaging target could visualize areas of increased inflammation. However, it is not yet fully understood if TSPO expression varies with inter-individual heterogeneity in GBM. We have investigated this in different preclinical models.

Methods: In a mouse model, primary human GBM cells and transgenic murine glioma cells (p53KOPDGFB, cdkn2aKOEGFRvIII) with different GBM subtype-specific characteristics were implanted orthotopically. After i.v. application of TSPO ligand 18F-GE-180 (n=20), cryosections and autoradiographies were prepared; Subsequently, immunostaining of the tumors for TSPO, LAT1, AIF1 (Iba1), CD31 and PDGFRB was performed. In addition, human tumor samples were analyzed in situ (n=12) and silico (TCGA database, n=488) for the expression of TSPO and AIF1.

Results: In all models (biopsies, mouse models and database query), there was a marked increase in TSPO expression in the tumor compared to the tumor-free brain. In the autoradiographies we observed an increased accumulation of tracer in the tumor area. By immunostaining we detected TSPO not only in tumor cells, but also TAM, endothelial cells and pericytes. The expression of the amino acid transporter LAT1, however, was largely restricted to tumor cells. In the TCGA data analysis, TSPO and AIF1 showed significantly different expression levels depending on the genetic subclass of the highest expressing mesenchymal subtype. High TSPO and high AIF1 expression correlated with a significantly poorer clinical outcome of the patients.

Conclusion: TSPO is expressed both in glioma cells and in tumor parenchyma. A combination of TSPO- and FET-PET might be a promising way to visualize inter- and intratumor heterogeneity and to visualize tumor-associated myeloid cells. GBM of the mesenchymal subtype, which accumulates more TAM, has the highest TSPO expression. Our study shows that mouse models can provide an important contribution to the interpretation of GBM imaging data.