Abstract
BackgroundO-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30% of low- and 5% of high-grade gliomas do not present enhanced 18F-FET uptake at primary diagnosis (“18F-FET-negative gliomas”) and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18F-FET-negative gliomas and to compare them to a matched group of 18F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18F-FET-negative (tumour-to-background ratio (TBR) < 1.6), n = 20 18F-FET-positive gliomas (TBR > 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells (%) and the staining intensity (range 0–2) were multiplied to an overall score (H-score; range 0–200) and correlated to PET findings as well as progression-free survival (PFS).ResultsIHC staining of LAT1 expression was positive in both, 18F-FET-positive as well as 18F-FET-negative gliomas. No differences were found between the 18F-FET-negative and 18F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBRmax, neither in the overall group nor in the 18F-FET-positive group only (p = 0.651 and p = 0.140).ConclusionAlthough LAT1 is reported to mediate the uptake of 18F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18F-FET are necessary.
Highlights
O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive Positron emission tomography (PET) tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1)
It has previously been described that the light chain LAT1 and 4F2 heavy chain (4F2hc) expression is positively correlated and it is assumed that the light chain LAT1 expression level corresponds to that of 4F2hc [10]
LAT1 is reported to mediate the uptake of 18FFET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18F-FET uptake in a homogeneous group of IDH-mutant astrocytomas WHO grade II/III
Summary
O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). LAT1 requires another cell surface glycoprotein, the 4F2 heavy chain (4F2hc), for its functional expression, and recent studies describe the importance for transport activity [8]. Together both proteins form a heterodimeric transport complex [9]. The upregulated expression of LAT1 may benefit by providing tumour cells with essential amino acids for high levels of protein synthesis associated with cell activation to support rapid growth or excessive proliferation. LAT1 has been described as a prognostic marker for malignant progression and proliferation of high-grade gliomas and correlates closely with the glioma angiogenesis [10, 16]
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