Review of the Correlation of LAT1 With Diseases: Mechanism and Treatment

Zhang, Jingshun; Xu, Ying; Li, Dandan; Fu, Li; Zhang, Xueying; Bao, Yi-Gang; Zheng, Lan

doi:10.3389/fchem.2020.564809

Cited by 48 publications

(35 citation statements)

References 156 publications

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“…The main function of the LAT1 protein is to help specific amino acids pass through the cell membrane to provide nutrients to cells and participate in metabolic pathways. LAT1 is over-expressed in many human cancer cells that are characterized by an increased demand of essential amino acids including gliomas [ 11 – 15 ]. 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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Hence, a lack of essential amino acid supply from dietary intake certainly gave rise to a pretreatment malnutrition status in patients with LAHNSCC. Second, the intimate relationship between histidine, leucine, and phenylalanine can be further strengthened by the fact that they share a common membrane transporter, L-type amino acid transporter 1 (LAT1), which is responsible for the delivery of histidine, phenylalanine, and branched-chain amino acids (BCAAs) into cells and is mainly related to protection against inflammatory stress [ 64 , 65 ]. LAT1 is usually over-expressed in patients with oral cavity squamous cell carcinoma [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Pretreatment Glasgow Prognostic Score Correlated with Serum Histidine Level and Three-Year Mortality of Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma and Optimal Performance Status

et al. 2022

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Few prospective cohort trials have investigted the effect of pretreatment nutritional and inflammatory status on the clinical outcome of patients with cancer and optimal performance status and assessed the interplay between nutrition, inflammation, body composition, and circulating metabolites before treatment. Here, 50 patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were prospectively recruited along with 43 healthy participants. Before concurrent chemoradiotherapy, compared with healthy controls, the cancer group showed lower levels of histidine, leucine, and phenylalanine and had low values in anthropometric and body composition measurements; however, the group displayed higher ornithine levels, more malnutrition, and severe inflammation. Pretreatment advanced Glasgow prognostic score (1 and 2) status was the sole prognostic factor for 3-year mortality rate and was associated with age and serum histidine levels in patients with cancer. Thus, even at the same tumor stage and ECOG PS, patients with LAHNSCC, poor nutrition, and high inflammation severity at baseline may have inferior survival outcomes than those with adequate nutrition and low inflammation severity. Assessment of pretreatment nutritional and inflammatory status should be included in the enrollment criteria in future studies.

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“…Changes in histidine and phenylalanine levels in patients with heart failure can be used to assess their responses to medications and nutritional interventions [49]. The transport of histidine and phenylalanine into cells requires L-type amino acid transporter 1 (LAT1), i.e., a membrane transporter responsible for transporting bulky amino acids, which is regulated by glutathione status and oxidative stress [103,104]. LAT1 is overexpressed in patients with oral cavity squamous-cell carcinoma [105].…”

Section: Discussionmentioning

confidence: 99%

Treatment-Interval Changes in Serum Levels of Albumin and Histidine Correlated with Treatment Interruption in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Completing Chemoradiotherapy under Recommended Calorie and Protein Provision

Wang

Ling

Liu

et al. 2022

Cancers

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We investigated risk factors for treatment interruption (TI) in patients with locally advanced head and neck squamous-cell carcinoma (LAHNSCC) following concurrent chemoradiotherapy (CCRT), under the provision of recommended calorie and protein intake; we also evaluated the associations between clinicopathological variables, calorie and protein supply, nutrition–inflammation biomarkers (NIBs), total body composition change (TBC), and a four-serum-amino-acid metabolite panel (histidine, leucine, ornithine, and phenylalanine) among these patients. Patients with LAHNSCC who completed the entire planned CCRT course and received at least 25 kcal/kg/day and 1 g of protein/kg/day during CCRT were prospectively recruited. Clinicopathological variables, anthropometric data, blood NIBs, CCRT-related factors, TBC data, and metabolite panels before and after treatment were collected; 44 patients with LAHNSCC were enrolled. Nine patients (20.4%) experienced TIs. Patients with TIs experienced greater reductions in hemoglobin, serum levels of albumin, uric acid, histidine, and appendicular skeletal mass, and suffered from more grade 3/4 toxicities than those with no TI. Neither increased daily calorie supply (≥30 kcal/kg/day) nor feeding tube placement was correlated with TI. Multivariate analysis showed that treatment-interval changes in serum albumin and histidine levels, but not treatment toxicity, were independently associated with TI. Thus, changes in serum levels of albumin and histidine over the treatment course could cause TI in patients with LAHNSCC following CCRT.

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Review of the Correlation of LAT1 With Diseases: Mechanism and Treatment

Cited by 48 publications

References 156 publications

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

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

Pretreatment Glasgow Prognostic Score Correlated with Serum Histidine Level and Three-Year Mortality of Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma and Optimal Performance Status

Treatment-Interval Changes in Serum Levels of Albumin and Histidine Correlated with Treatment Interruption in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Completing Chemoradiotherapy under Recommended Calorie and Protein Provision

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