Influx rate of 18F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts
- 43 Downloads
18F-fluoroaminosuberic acid (18F-FASu) is a recently developed amino acid tracer for positron emission tomography (PET) of oxidative stress that may offer improved tumour assessment over the conventional tracer 18F-fluorodeoxyglucose (18F-FDG). Our aim was to evaluate and relate dynamic 18F-FASu and 18F-FDG uptake with pharmacokinetic modelling to transporter protein expression levels in a panel of diverse tumour xenograft lines.
Four different tumour xenograft lines were implanted in female athymic nude mice: MAS98.12 and HBCx3 (breast), TPMX (osteosarcoma) and A549 (lung). Dynamic PET over 60 min was performed on a small animal unit. The time–activity curves (TACs) for 18F-FASu and 18F-FDG in individual tumours were used to extract early (SUVE; 2 min p.i.) and late (SUVL; 55 min p.i.) standardised uptake values. Pharmacokinetic two-tissue compartment models were applied to the TACs to estimate rate constants K1–k4 and blood volume fraction vB. Relative levels of cystine/glutamate antiporter subunit xCT were assessed by western blotting, and expression of GLUT1 and CD31 by immunohistochemistry.
18F-FASu showed higher SUVE, whilst 18F-FDG exhibited higher SUVL. Influx rate K1 for 18F-FASu was significantly correlated with xCT levels (p = 0.001) and was significantly higher than K1 for 18F-FDG (p < 0.001). K1 for 18F-FDG was significantly correlated with GLUT1 levels (p = 0.002). vB estimated from 18F-FASu and 18F-FDG TACs was highly consistent and significantly correlated (r = 0.85, p < 0.001). Two qualitatively different 18F-FASu uptake profiles were identified: type α with low xCT expression and low K1 (A549 and HBCx3), and type β with high xCT expression and high K1 (MAS98.12 and TPMX).
The influx rate of 18F-FASu reflects xCT activity in tumour xenografts. Dynamic PET with pharmacokinetic modelling is needed to fully appraise 18F-FASu distribution routes.
KeywordsCancer Xenograft Mouse model System XC− xCT 18F-fluoroaminosuberic acid 18F-FDG Dynamic PET Pharmacokinetic modelling Oxidative stress
This study was funded by the University of Oslo (convergence grants) and the Norwegian Cancer Society (grant 6871141-2015).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 1.Inoue T, Kim EE, Komaki R, Wong FCL, Bassa P, Wong W-H, et al. Detecting recurrent or residual lung cancer with FDG-PET. J Nucl Med. 1995;36:788–93.Google Scholar
- 4.Gulyas B, Halldin C. New PET radiopharmaceuticals beyond FDG for brain tumor imaging. Q J Nucl Med Mol Imaging. 2012;56:173–90.Google Scholar
- 7.Baek S, Choi C-M, Ahn SH, Lee JW, Gong G, Ryu J-S, et al. Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-l-glutamate for imaging xC− transporter using positron emission tomography in patients with non–small cell lung or breast Cancer. Clin Cancer Res. 2012;18:5427–37. https://doi.org/10.1158/1078-0432.ccr-12-0214.CrossRefGoogle Scholar
- 10.Yang H, Miao Q, Jenni S, Čolović M, Johnson B, Rishel M, et al. [18F] 5-fluoro aminosuberic acid (FASu) for oxidative stress imaging in breast cancer. J Nucl Med. 2015;56:1176.Google Scholar
- 16.Koeppe RA, Frey KA, Vander Borght TM, Karlamangla A, Jewett DM, Lee LC, et al. Kinetic evaluation of [11C]Dihydrotetrabenazine by dynamic PET: measurement of vesicular monoamine transporter. J Cereb Blood Flow Metab. 1996;16:1288–99. https://doi.org/10.1097/00004647-199611000-00025.CrossRefGoogle Scholar
- 23.Bretschi M, Cheng C, Witt H, Dimitrakopoulou-Strauss A, Strauss LG, Semmler W, et al. Cilengitide affects tumor compartment, vascularization and microenvironment in experimental bone metastases as shown by longitudinal 18F-FDG PET and gene expression analysis. J Cancer Res Clin Oncol. 2013;139:573–83. https://doi.org/10.1007/s00432-012-1360-6.CrossRefGoogle Scholar
- 26.Koppula P, Zhang Y, Shi J, Li W, Gan B. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J Biol Chem 2017:jbc. M117. 798405.Google Scholar
- 28.Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N, et al. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene. 2007;27:1618. https://doi.org/10.1038/sj.onc.1210796 https://www.nature.com/articles/1210796#supplementary-information.CrossRefGoogle Scholar