L-type amino acid transporters LAT1 and LAT4 in cancer: uptake of 3-O-methyl-6-18F-fluoro-L-dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo.
Expression of system L amino acid transporters (LAT) is strongly increased in many types of tumor cells. The purpose of this study was to demonstrate that (18)F-labeled amino acids, for example, 3-O-methyl-6-(18)F-fluoro-L-dopa ((18)F-OMFD), that accumulate in tumors via LAT represent an important class of imaging agents for visualization of tumors in vivo by PET.


METHODS
(18)F-OMFD uptake kinetics, transport inhibition, and system L messenger RNA expression were studied in vitro in human adenocarcinoma (HT-29), squamous cell carcinoma (FaDu), macrophages (THP-1), and primary aortic endothelial cells (HAEC) and in vivo in the corresponding mouse tumor xenograft models.


RESULTS
Uptake of (18)F-OMFD in all cell lines tested was mediated mainly by the sodium-independent high-capacity LAT. We found higher uptake in FaDu cells (V(max), 10.6 +/- 1.1 nmol/min x mg of cell protein) and in the corresponding FaDu tumor xenografts than in the other cells and corresponding xenograft models studied. Quantitative messenger RNA analysis revealed that tumor cells and xenografts have a higher expression of LAT1 than do HAEC and THP-1 macrophages. However, only in the FaDu tumor model did an increased (18)F-OMFD uptake seem to be explained by increased LAT expression. Furthermore, we demonstrated a high expression of LAT4, a recently identified LAT.


CONCLUSIONS
Our findings support the hypothesis that (18)F-OMFD is a tracer for visualization of tumor cells. (18)F-OMFD particularly seems to be a suitable tracer for diagnostic imaging of amino acid transport in poorly differentiated squamous cell head and neck carcinoma with increased LAT1 and LAT4 expression.
Haase
Cathleen
C
Department of Radiopharmaceutical Biology, Institute of Radiopharmacy, Research Center Dresden-Rossendorf, Dresden, Germany. c.haase@fzd.de
Bergmann
Ralf
R
Fuechtner
Frank
F
Hoepping
Alexander
A
Pietzsch
Jens
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000378:metabolism*; D027062:Amino Acid Transport System L / Q000235:genetics*; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes; D027261:Fusion Regulatory Protein-1 / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D027062:Amino Acid Transport System L; D026923:Amino Acid Transport Systems, Basic; D005462:Fluorine Radioisotopes; D027261:Fusion Regulatory Protein-1; C419196:LAT2 protein, human; D027283:Large Neutral Amino Acid-Transporter 1; D012333:RNA, Messenger; C469951:SLC7A6 protein, human; C055151:3-O-methyl-6-fluoro-dopa; D004295:Dihydroxyphenylalanine