Study of LAT1 Expression in Brain Metastases: Towards a Better Understanding of the Results of Positron Emission Tomography Using Amino Acid Tracers

Abstract

Positron emission tomography using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumour and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to determine and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochemistry in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5% and 59.7% of BM respectively and were significantly associated with BM tissue as compared to NT (p<0.001). LAT1 expression in recurrent BM was significantly increased as compared to newly occurring BM. Ten cases investigated by [18F] FDOPA-PET corresponding to recurrent BM displayed significant [18F] FDOPA uptake and LAT1 overexpression whereas three cases corresponding to radionecrosis showed no or low uptake and LAT1 expression. LAT1 expression level and [18F] FDOPA uptake were significantly correlated. In conclusion, we hypothesized that BM may overexpress the AA transporter LAT1. We have shown that LAT1 overexpression was common in BM and was specific for BM as compared to healthy brain. These results could explain the specific BM uptake on PET-AA.

18F-FET PET Uptake Characteristics in Patients with Newly Diagnosed and Untreated Brain Metastasis

“…Our results therefore suggest that 18 F-FETnegative findings may also occur in brain metastases (in our study in one third of metastases # 1.0 cm) but might mostly be related to partial-volume effects and limited scanner resolution, leading to underestimation of 18 F-FET uptake especially in tumors with low tracer uptake, rather than to a complete lack of 18 F-FET uptake as observed in 30% of low-grade gliomas (14,26). This might especially be the case because a missing expression of the L-amino-acid transporter, responsible for 18 F-FET uptake in brain metastases, was reported to be a rare condition itself (27). Therefore, pursuing the 18 F-FET PET assessment of metastases with a diameter ce of , 1.0 cm is of limited value, because a negative finding not necessarily excludes viable tumor.…”

“…Also a mere 18 F-FET influx through the disrupted BBB can be excluded (30), because a BBB disruption is also seen in nontumorous lesions such as radionecrosis, but without pathologic 18 F-FET uptake (16). Therefore, as in gliomas, tumoral 18 F-FET uptake in metastases is also attributed to the L-amino-acid transporter (27).…”

Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake

“…LAT1 is also overexpressed in various cancer cells, including breast cancer, nonsmall cell lung cancer and glioblastoma multiforme (Furuya, et al 2012;Kaira, et al 2008a;Kobayashi, et al 2008). The functional level of LAT1 correlates with cancer progression; metastases and high grade tumors express greater amounts of LAT1 (Furuya, et al 2012;Kaira, et al 2008b;Papin-Michault, et al 2016). Moreover, cancer cell proliferation decreases when the function of the LAT1 is inhibited (Huttunen, et al 2016b;Oda, et al 2010;Shennan and Thomson 2008).…”

The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy

“…FDOPA is currently approved for characterization of presynaptic dopaminergic activity in patients with Parkinsonian syndromes in the United States and Western Europe. The increased uptake of MET, FET and FDOPA in gliomas and brain metastases appears to be caused predominantly by increased transport via the amino acid transport system L for large neutral amino acids namely the subtypes LAT1 and LAT2 (Okubo et al, 2010, Papin-Michault et al, 2016, Wiriyasermkul et al, 2012, Youland et al, 2013). A feature that distinguishes FET from MET and FDOPA is the high metabolic stability of FET.…”