Correlation between 18F-1-amino-3-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) uptake and expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter 1 (LAT1) in primary prostate cancer

Abstract

Purpose To evaluate the expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter1 (LAT1) in prostate cancer (PCa) and their impact on uptake of 18 F-1-amino-3-fluorocyclobutane-1-carboxylic acid ( 18 F-fluciclovine) which is approved for the detection of recurrent PCa. Methods Twenty-five hormone-naïve patients with histologically confirmed PCa underwent PET/CT before prostatectomy. Dynamic imaging was performed immediately after injection of 368 ± 10 MBq of 18 F-fluciclovine and the uptake in PCa was expressed as SUV max at six sequential 4-min time frames and as tracer distribution volume ( V T ) using Logan plots over 0–24 min. The expression of ASCT2 and LAT1 was studied with immunohistochemistry (IHC) on a tissue microarray (TMA) containing three cores per carcinoma lesion. The TMA slides were scored independently by two trained readers based on visual intensity of ASCT2/LAT1 expression on a four-tiered scale. The correlations between ASCT2/LAT1 staining intensity, SUVmax/ V T , and Gleason grade group (GGG) were assessed using Spearman’s rank correlation coefficient ( ρ ). Results Forty tumor foci (> 0.5 mm in diameter, max. 3 per patient) were available for TMA. In visual scoring, low, moderate, and high staining intensity of ASCT2 was observed in 4 (10%), 24 (60%), and 12 (30%) tumors, respectively. No tumors showed high LAT1 staining intensity while moderate intensity was found in 10 (25%), 25 (63%) showed low, and the remaining 5 (12%) were negative for staining with LAT1. Tumors with GGG > 2 showed significantly higher uptake of 18 F-fluciclovine and higher LAT1 staining intensity ( p < 0.05). The uptake of 18 F-fluciclovine correlated significantly with LAT1 expression ( ρ = 0.39, p = 0.01, for SUV max at 2 min and ρ = 0.39, p = 0.01 for V T ). No correlation between ASCT2 expression and 18 F-fluciclovine uptake or GGG was found. Conclusions Our findings suggest that LAT1 is moderately associated with the transport of 18 F-fluciclovine in local PCa not exposed to hormonal therapy. Both high and low Gleason grade tumors express ASCT2 while LAT1 expression is less conspicuous and may be absent in some low-grade tumors. Our observations may be of importance when using 18 F-fluciclovine imaging in the planning of focal therapies for PCa.

18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy

“…The 'yingyang' pattern of LAT1 expression between androgensensitive and castration-resistant states observed in our study fits with what has been previously reported [28]. More recently, consistent with our findings, high levels of LAT1 expression in resected prostate tumours positively and significantly correlated with tumoral 18 F-Fluciclovine uptake [8]. Hence, the in vivo model of CRPC presented here mimics clinical disease and further builds on previously studies based on in vitro models.…”

“…LAT1 is a sodium independent exchange amino acid transporter (AAT) between intracellular and extracellular environments [7]. In contrast, ASCT2 mediates amino acid uptake in a sodium-dependent manner [7,8]. As a leucine analogue, 18 F-Fluciclovine is not incorporated into proteins, but its uptake mirrors that of glutamine [6,9], which plays a key role in cancer metabolism [7].…”

Amino Acid Transporters on the Guard of Cell Genome and Epigenome

“…A preclinical study using PCa cell lines showed that upregulation of SLC1A5 expression in response to dihydrotestosterone (DHT) treatment correlates with increased uptake of [ 14 C]fluciclovine, a tracer for the imaging of PCa [ 216 ]. However, analysis of ( 18 F)fluciclovine PET scans of hormone naïve PCa patients demonstrates that ( 18 F)fluciclovine uptake does not correlate with SLC1A5 expression [ 217 ]. Given the emerging role of SLC1A5 as a promising cancer biomarker, SLC1A5-specific tracers could be further developed into precision PET imaging diagnostic tools.…”

“…The SLC7A5 overexpression is associated with high uptake of ( 18 F)-FDOPA, whereas radionecrosis regions with low SLC7A5 expression are characterized by an absence of ( 18 F)-FDOPA signal [ 226 ]. The level of SLC7A5 expression significantly correlates with ( 18 F)fluciclovine uptake by tumor tissues in patients with hormone naïve PCa, and tumors with high Gleason grade have higher SLC7A5 expression and 18 F-fluciclovine signal [ 217 ].…”

Next Generation Imaging Techniques to Define Immune Topographies in Solid Tumors

“…Fluciclovine 18 F-FACBC, an analog of L-leucine, is a radiolabeled amino acid that is imported into activated T-cells due to upregulation of the amino acid transporter ASCT2 and LAT-1 ( 373 – 375 , 400 , 401 ). Labeled substrates for enzymes involved in the deoxyrubonucleoside salvage pathway have been developed such as 18 F-FAC, 18 F -CFA, 18 F-FLT, and 18 F-F-AraG ( 318 ).…”