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

Haase, Cathleen; Bergmann, Ralf; Fuechtner, Frank; Hoepping, Alexander; Pietzsch, Jens

doi:10.2967/jnumed.107.043620

Cited by 72 publications

(49 citation statements)

References 33 publications

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“…The latter is, however, not typically overexpressed in cancer cells (33). 18 F-FDOPA influx into MDA-MB-231 nonendocrine cells was almost completely blocked by BCH, also suggesting LAT1 or LAT2 as the major uptake mechanism.…”

Section: Discussionmentioning

confidence: 88%

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Krämer¹,

Mu²,

Müller³

et al. 2012

J Nucl Med

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Large neutral L-amino acids are substrates of system L amino acid transporters. The level of one of these, LAT1, is increased in many tumors. Aromatic L-amino acids may also be substrates of aromatic L-amino acid decarboxylase (AADC), the level of which is enhanced in endocrine tumors. Increased amino acid uptake and subsequent decarboxylation result in the intracellular accumulation of the amino acid and its decarboxylation product. 18 F-and 11 C-labeled neutral aromatic amino acids, such as L-3,4-dihydroxy-6-18 F-fluorophenylalanine ( 18 F-FDOPA) and 5-hydroxy-L-[b-11 C]tryptophan, are thus successfully used in PET to image endocrine tumors. However, 5-hydroxy-L-[b-11 C]tryptophan has a relatively short physical half-life (20 min). In this work, we evaluated the in vitro and in vivo characteristics of the 18 F-labeled tryptophan analog 5-(2-18 F-fluoroethoxy)-L-tryptophan ( 18 F-L-FEHTP) as a PET probe for tumor imaging. Methods: 18 F-L-FEHTP was synthesized by no-carrier-added 18 F fluorination of 5-hydroxy-L-tryptophan. In vitro cell uptake and efflux of 18 F-L-FEHTP and 18 F-FDOPA were studied with NCI-H69 endocrine small cell lung cancer cells, PC-3 pseudoendocrine prostate cancer cells, and MDA-MB-231 exocrine breast cancer cells. Small-animal PET was performed with the respective xenograft-bearing mice. Tissues were analyzed for potential metabolites. Results: 18 F-L-FEHTP specific activity and radiochemical purity were 50-150 GBq/mmol and greater than 95%, respectively. In vitro cell uptake of 18 F-L-FEHTP was between 48% and 113% of added radioactivity per milligram of protein within 60 min at 37°C and was blocked by greater than 95% in all tested cell lines by the LAT1/2 inhibitor 2-amino-2-norboranecarboxylic acid. 18 F-FDOPA uptake ranged from 26% to 53%/mg. PET studies revealed similar xenograft-to-reference tissue ratios for 18 F-L-FEHTP and 18 F-FDOPA at 30-45 min after injection. In contrast to the 18 F-FDOPA PET results, pretreatment with the AADC inhibitor S-carbidopa did not affect the 18 F-L-FEHTP PET results. No decarboxylation products of 18 F-L-FEHTP were detected in the xenograft homogenates. Conclusion: 18 F-L-FEHTP accumulates in endocrine and nonendocrine tumor models via LAT1 transport but is not decarboxylated by AADC. 18 F-L-FEHTP may thus serve as a PET probe for tumor imaging and quantification of tumor LAT1 activity. These findings are of interest in view of the ongoing evaluation of LAT1 substrates and inhibitors for cancer therapy.

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Section: Discussionmentioning

confidence: 88%

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Krämer¹,

Mu²,

Müller³

et al. 2012

J Nucl Med

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“…Some genes in SLC family are cancer-related, for example, SLC43A2 whose overexpression is associated with the adenocarcinomas and squamous cell carcinoma [45], which was identified in the previous work [16]. …”

Section: Resultsmentioning

confidence: 99%

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Gong

Clarke

2014

BMC Systems Biology

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BackgroundRecent global genomic analyses identified 69 gene sets and 12 core signaling pathways genetically altered in pancreatic cancer, which is a highly malignant disease. A comprehensive understanding of the genetic signatures and signaling pathways that are directly correlated to pancreatic cancer survival will help cancer researchers to develop effective multi-gene targeted, personalized therapies for the pancreatic cancer patients at different stages. A previous work that applied a LASSO penalized regression method, which only considered individual genetic effects, identified 12 genes associated with pancreatic cancer survival.ResultsIn this work, we integrate pathway information into pancreatic cancer survival analysis. We introduce and apply a doubly regularized Cox regression model to identify both genes and signaling pathways related to pancreatic cancer survival.ConclusionsFour signaling pathways, including Ion transport, immune phagocytosis, TGFβ (spermatogenesis), regulation of DNA-dependent transcription pathways, and 15 genes within the four pathways are identified and verified to be directly correlated to pancreatic cancer survival. Our findings can help cancer researchers design new strategies for the early detection and diagnosis of pancreatic cancer.

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“…LAT1 is physiologically expressed in many human tissues, including the brain, where it mediates transport of neutral amino acids across the blood-brain barrier (164). LAT1 is also highly expressed in a variety of tumors and tumor cell lines of various origins (167)(168)(169). In a series of 321 patients with surgically treated non-small cell lung cancer, LAT1 protein expression as determined by immunohistochemistry was more frequently found in squamous cell carcinoma than in adenocarcinoma (170).…”

Section: Amino Acid Transportmentioning

confidence: 99%

Tumor Cell Metabolism Imaging

Plathow¹,

Weber²

2008

J Nucl Med

278

222

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Molecular imaging of tumor metabolism has gained considerable interest, since preclinical studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism. Furthermore, several clinical trials have shown that metabolic imaging can significantly impact patient management by improving tumor staging, restaging, radiation treatment planning, and monitoring of tumor response to therapy. In this review, we summarize recent data on the molecular mechanisms underlying the increased metabolic activity of cancer cells and discuss imaging techniques for studies of tumor glucose, lipid, and amino acid metabolism.

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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

Cited by 72 publications

References 33 publications

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Tumor Cell Metabolism Imaging

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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

Cited by 72 publications

References 33 publications

5-(2-18F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

5-(2-18F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Tumor Cell Metabolism Imaging

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5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET