L-type amino acid transporter (LAT) 1 expression in 18F-FET-negative gliomas

Abstract

Background 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). 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). Results IHC 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). Conclusion Although 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.

Recapitulating the Key Advances in the Diagnosis and Prognosis of High-Grade Gliomas: Second Half of 2021 Update

“…It has been suggested that 18 F-FET uptake is linked to the action of L1 amino acid transporter (LAT1). However, 5% of HGG do not capture 18 F-FET (“ 18 F-FET-negative gliomas”), and the pathophysiological basis of this phenomenon has been studied by Vettermann et al [ 30 ]. No relationship was observed between the LAT1 levels and tumor uptake capacity, suggesting that the possible lack of 18 F-FET uptake is not due to the poor expression of LAT1.…”

PET Imaging in Neuro-Oncology: An Update and Overview of a Rapidly Growing Area

“…The three most widely used amino acid PET radiotracers, namely 11C-methyl-methionine ( 11 C-MET), O-(2-[18F]-fluoroethyl)-L-tyrosine ( 18 F-FET) and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine ( 18 F-FDOPA), the latter with a physiological uptake in the basal ganglia, enter cells through the L-amino acid transporters that are overexpressed in gliomas and brain metastases [ 8 , 9 , 10 ]. However, L-amino acid transporter expression was still present in photopenic gliomas on 18 F-FET, making it less clear what drives amino acid uptake [ 11 ]. The transport and uptake of amino acid PET radiotracers are independent of the blood brain barrier.…”

Recent Advances in 18F-Labeled Amino Acids Synthesis and Application

“…However, due to high uptake in the normal brain, [ 18 F]FDG is met with limited success in acquiring images with adequate contrast in brain tumors [ 5 ]. Moreover, some types of tumors may transform their metabolic consumption from glucose to other nutrients such as amino acids (AAs) [ 6 , 7 ].…”