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.
Department of Radiopharmaceutical Biology, Institute of Radiopharmacy, Research Center Dresden-Rossendorf, Dresden, Germany. c.haase@fzd.de
Cathleen
C
Haase
Ralf
R
Bergmann
Frank
F
Fuechtner
Alexander
A
Hoepping
Jens
J
Pietzsch
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