Skip to main content
Top
Published in: Journal of Nuclear Cardiology 5/2021

Open Access 01-10-2021 | Computed Tomography | Original Article

Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm

Authors: Richa Gandhi, MSc, Christopher Cawthorne, PhD, Lucinda J. L. Craggs, PhD, John D. Wright, MSc, Juozas Domarkas, PhD, Ping He, PhD, Joanna Koch-Paszkowski, MSc, Michael Shires, Andrew F. Scarsbrook, BMBS, Stephen J. Archibald, PhD, Charalampos Tsoumpas, PhD, Marc A. Bailey, MB, ChB, PhD

Published in: Journal of Nuclear Cardiology | Issue 5/2021

Login to get access

Abstract

Background

Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([18F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion).

Methods and Results

Fourteen-week-old apolipoprotein E-knockout (ApoE−/−) mice received saline or AngII via osmotic mini-pumps for 14 (n = 7 and 5, respectively) or 28 (n = 3 and 4, respectively) days and underwent 90-minute dynamic [18F]FLT PET/CT. Organs were harvested from independent cohorts for gamma counting, ultrasound scanning, and western blotting. [18F]FLT uptake was significantly greater in 14- (n = 5) and 28-day (n = 3) AAA than in saline control aortae (n = 5) (P < 0.001), which reduced between days 14 and 28. Whole-organ gamma counting confirmed greater [18F]FLT uptake in 14-day AAA (n = 9) compared to saline-infused aortae (n = 4) (P < 0.05), correlating positively with aortic volume (r = 0.71, P < 0.01). Fourteen-day AAA tissue showed increased expression of thymidine kinase-1, equilibrative nucleoside transporter (ENT)-1, ENT-2, concentrative nucleoside transporter (CNT)-1, and CNT-3 than 28-day AAA and saline control tissues (n = 3 each) (all P < 0.001).

Conclusions

[18F]FLT uptake is increased during the active growth phase of the AAA model compared to saline control mice and late-stage AAA.
Appendix
Available only for authorised users
Literature
1.
go back to reference Blanchard JF, Armenian HK, Friesen PP. Risk factors for abdominal aortic aneurysm: Results of a case-control study. Am J Epidemiol 2000;151:575-83.CrossRef Blanchard JF, Armenian HK, Friesen PP. Risk factors for abdominal aortic aneurysm: Results of a case-control study. Am J Epidemiol 2000;151:575-83.CrossRef
2.
go back to reference Chichester Aneurysm Screening Group, Viborg Aneurysm Screening Study, Western Australian Abdominal Aortic Aneurysm Program, Multicentre Aneurysm Screening Study. A comparative study of the prevalence of abdominal aortic aneurysms in the United Kingdom, Denmark, and Australia. J Med Screen 2001;8:46-50.CrossRef Chichester Aneurysm Screening Group, Viborg Aneurysm Screening Study, Western Australian Abdominal Aortic Aneurysm Program, Multicentre Aneurysm Screening Study. A comparative study of the prevalence of abdominal aortic aneurysms in the United Kingdom, Denmark, and Australia. J Med Screen 2001;8:46-50.CrossRef
3.
go back to reference Zucker EJ, Misono AS, Prabhakar AM. Abdominal aortic aneurysm screening practices: Impact of the 2014 U.S. Preventive Services Task Force Recommendations. J Am Coll Radiol 2017;14:868-74.CrossRef Zucker EJ, Misono AS, Prabhakar AM. Abdominal aortic aneurysm screening practices: Impact of the 2014 U.S. Preventive Services Task Force Recommendations. J Am Coll Radiol 2017;14:868-74.CrossRef
4.
go back to reference Sweeting MJ, Thompson SG, Brown LC, Powell JT. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 2012;99:655-65.CrossRef Sweeting MJ, Thompson SG, Brown LC, Powell JT. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 2012;99:655-65.CrossRef
5.
go back to reference Powell JT, Brown LC, Forbes JF, et al. Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial. Br J Surg 2007;94:702-8.CrossRef Powell JT, Brown LC, Forbes JF, et al. Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial. Br J Surg 2007;94:702-8.CrossRef
6.
go back to reference Sakalihasan N, Van Damme H, Gomez P, et al. Positron emission tomography (PET) evaluation of abdominal aortic aneurysm (AAA). Eur J Vasc Endovasc Surg 2002;23:431-6.CrossRef Sakalihasan N, Van Damme H, Gomez P, et al. Positron emission tomography (PET) evaluation of abdominal aortic aneurysm (AAA). Eur J Vasc Endovasc Surg 2002;23:431-6.CrossRef
7.
go back to reference Nie M-X, Zhang X-H, Yan Y-F, Zhao Q-M. Relationship between inflammation and progression of an abdominal aortic aneurysm in a rabbit model based on 18F-FDG PET/CT imaging. Vascular 2018;26:571-80.CrossRef Nie M-X, Zhang X-H, Yan Y-F, Zhao Q-M. Relationship between inflammation and progression of an abdominal aortic aneurysm in a rabbit model based on 18F-FDG PET/CT imaging. Vascular 2018;26:571-80.CrossRef
8.
go back to reference English SJ, Piert MR, Diaz JA, et al. Increased (18)F-FDG uptake is predictive of rupture in a novel rat abdominal aortic aneurysm rupture model. Ann Surg 2015;261:395-404.CrossRef English SJ, Piert MR, Diaz JA, et al. Increased (18)F-FDG uptake is predictive of rupture in a novel rat abdominal aortic aneurysm rupture model. Ann Surg 2015;261:395-404.CrossRef
9.
go back to reference Huang Y, Teng Z, Elkhawad M, et al. High structural stress and presence of intraluminal thrombus predict abdominal aortic aneurysm 18F-FDG uptake: Insights from biomechanics. Circ Cardiovasc Imaging 2016;9:e004656.CrossRef Huang Y, Teng Z, Elkhawad M, et al. High structural stress and presence of intraluminal thrombus predict abdominal aortic aneurysm 18F-FDG uptake: Insights from biomechanics. Circ Cardiovasc Imaging 2016;9:e004656.CrossRef
10.
go back to reference Reeps C, Essler M, Pelisek J, et al. Increased 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J Vasc Surg 2008;48:417-23.CrossRef Reeps C, Essler M, Pelisek J, et al. Increased 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J Vasc Surg 2008;48:417-23.CrossRef
11.
go back to reference Courtois A, Nusgens BV, Hustinx R, et al. 18F-FDG uptake assessed by PET/CT in abdominal aortic aneurysms is associated with cellular and molecular alterations prefacing wall deterioration and rupture. J Cardiovasc Surg 2013;54:1740-7. Courtois A, Nusgens BV, Hustinx R, et al. 18F-FDG uptake assessed by PET/CT in abdominal aortic aneurysms is associated with cellular and molecular alterations prefacing wall deterioration and rupture. J Cardiovasc Surg 2013;54:1740-7.
12.
go back to reference Nchimi A, Cheramy-Bien JP, Gasser TC, et al. Multifactorial relationship between 18F-fluoro-deoxy-glucose positron emission tomography signaling and biomechanical properties in unruptured aortic aneurysms. Circ Cardiovasc Imaging 2014;7:82-91.CrossRef Nchimi A, Cheramy-Bien JP, Gasser TC, et al. Multifactorial relationship between 18F-fluoro-deoxy-glucose positron emission tomography signaling and biomechanical properties in unruptured aortic aneurysms. Circ Cardiovasc Imaging 2014;7:82-91.CrossRef
13.
go back to reference Kotze CW, Groves AM, Menezes LJ, et al. What is the relationship between (1)(8)F-FDG aortic aneurysm uptake on PET/CT and future growth rate? Eur J Nucl Med Mol Imaging 2011;38:1493-9.CrossRef Kotze CW, Groves AM, Menezes LJ, et al. What is the relationship between (1)(8)F-FDG aortic aneurysm uptake on PET/CT and future growth rate? Eur J Nucl Med Mol Imaging 2011;38:1493-9.CrossRef
14.
go back to reference Barwick TD, Lyons OT, Mikhaeel NG, Waltham M, O’Doherty MJ. 18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size. Eur J Nucl Med Mol Imaging 2014;41:2310-8.CrossRef Barwick TD, Lyons OT, Mikhaeel NG, Waltham M, O’Doherty MJ. 18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size. Eur J Nucl Med Mol Imaging 2014;41:2310-8.CrossRef
15.
go back to reference Forsythe RO, Dweck MR, McBride OMB, et al. (18)F-sodium fluoride uptake in abdominal aortic aneurysms: The SoFIA(3) study. J Am Coll Cardiol 2018;71:513-23.CrossRef Forsythe RO, Dweck MR, McBride OMB, et al. (18)F-sodium fluoride uptake in abdominal aortic aneurysms: The SoFIA(3) study. J Am Coll Cardiol 2018;71:513-23.CrossRef
16.
go back to reference Maegdefessel L, Azuma J, Toh R, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med 2012;4:122ra122-122ra122.CrossRef Maegdefessel L, Azuma J, Toh R, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med 2012;4:122ra122-122ra122.CrossRef
17.
go back to reference Ailawadi G, Moehle CW, Pei H, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg 2009;138:1392-9.CrossRef Ailawadi G, Moehle CW, Pei H, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg 2009;138:1392-9.CrossRef
18.
go back to reference Salmon M, Johnston WF, Woo A, et al. KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation. Circulation 2013;128:S163-74.CrossRef Salmon M, Johnston WF, Woo A, et al. KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation. Circulation 2013;128:S163-74.CrossRef
19.
go back to reference Bridge K, Revill C, Macrae F, et al. Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms. PLoS ONE 2017;12:e0177117.CrossRef Bridge K, Revill C, Macrae F, et al. Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms. PLoS ONE 2017;12:e0177117.CrossRef
21.
go back to reference Miller I, Min M, Yang C, et al. Ki67 is a graded rather than a binary marker of proliferation versus quiescence. Cell Rep 2018;24:1105-12.CrossRef Miller I, Min M, Yang C, et al. Ki67 is a graded rather than a binary marker of proliferation versus quiescence. Cell Rep 2018;24:1105-12.CrossRef
22.
go back to reference Paproski RJ, Ng AML, Yao SYM, et al. The role of human nucleoside transporters in uptake of 3′-deoxy-3′-fluorothymidine. Mol Pharmacol 2008;74:1372.CrossRef Paproski RJ, Ng AML, Yao SYM, et al. The role of human nucleoside transporters in uptake of 3′-deoxy-3′-fluorothymidine. Mol Pharmacol 2008;74:1372.CrossRef
23.
go back to reference Paproski RJ, Wuest M, Jans H-S, et al. Biodistribution and uptake of 3′-deoxy-3′-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model. J Nucl Med 2010;51:1447-55.CrossRef Paproski RJ, Wuest M, Jans H-S, et al. Biodistribution and uptake of 3′-deoxy-3′-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model. J Nucl Med 2010;51:1447-55.CrossRef
24.
go back to reference Shields AF, Grierson JR, Dohmen BM, et al. Imaging proliferation in vivo with [F-18] FLT and positron emission tomography. Nat Med 1998;4:1334.CrossRef Shields AF, Grierson JR, Dohmen BM, et al. Imaging proliferation in vivo with [F-18] FLT and positron emission tomography. Nat Med 1998;4:1334.CrossRef
25.
go back to reference Barthel H, Cleij MC, Collingridge DR, et al. 3’-deoxy-3’-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791-8.PubMed Barthel H, Cleij MC, Collingridge DR, et al. 3’-deoxy-3’-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791-8.PubMed
26.
go back to reference Viertl D, Delaloye AB, Lanz B, et al. Increase of [18 F] FLT tumor uptake in vivo mediated by FdUrd: Toward improving cell proliferation positron emission tomography. Mol Imaging Biol 2011;13:321-31.CrossRef Viertl D, Delaloye AB, Lanz B, et al. Increase of [18 F] FLT tumor uptake in vivo mediated by FdUrd: Toward improving cell proliferation positron emission tomography. Mol Imaging Biol 2011;13:321-31.CrossRef
27.
go back to reference Salskov A, Tammisetti VS, Grierson J, Vesselle H. FLT: Measuring tumor cell proliferation in vivo with positron emission tomography and 3’-deoxy-3’-[18F]fluorothymidine. Semin Nucl Med 2007;37:429-39.CrossRef Salskov A, Tammisetti VS, Grierson J, Vesselle H. FLT: Measuring tumor cell proliferation in vivo with positron emission tomography and 3’-deoxy-3’-[18F]fluorothymidine. Semin Nucl Med 2007;37:429-39.CrossRef
28.
go back to reference Yue J, Chen L, Cabrera AR, et al. Measuring tumor cell proliferation with 18F-FLT PET during radiotherapy of esophageal squamous cell carcinoma: A pilot clinical study. J Nucl Med 2010;51:528-34.CrossRef Yue J, Chen L, Cabrera AR, et al. Measuring tumor cell proliferation with 18F-FLT PET during radiotherapy of esophageal squamous cell carcinoma: A pilot clinical study. J Nucl Med 2010;51:528-34.CrossRef
29.
go back to reference Ye YX, Calcagno C, Binderup T, et al. Imaging macrophage and hematopoietic progenitor proliferation in atherosclerosis. Circ Res 2015;117:835-45.CrossRef Ye YX, Calcagno C, Binderup T, et al. Imaging macrophage and hematopoietic progenitor proliferation in atherosclerosis. Circ Res 2015;117:835-45.CrossRef
30.
go back to reference Barthel H, Perumal M, Latigo J, et al. The uptake of 3’-deoxy-3’-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels. Eur J Nucl Med Mol Imaging 2005;32:257-63.CrossRef Barthel H, Perumal M, Latigo J, et al. The uptake of 3’-deoxy-3’-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels. Eur J Nucl Med Mol Imaging 2005;32:257-63.CrossRef
31.
go back to reference Seitz U, Wagner M, Neumaier B, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3’-[18F]fluoro-3’-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29:1174-81.CrossRef Seitz U, Wagner M, Neumaier B, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3’-[18F]fluoro-3’-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29:1174-81.CrossRef
32.
go back to reference Bagegni N, Thomas S, Liu N, et al. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res 2017;19:123.CrossRef Bagegni N, Thomas S, Liu N, et al. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res 2017;19:123.CrossRef
33.
go back to reference Mao Y, Wu J, Skog S, et al. Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling. Oncol Rep 2005;13:837-46.PubMed Mao Y, Wu J, Skog S, et al. Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling. Oncol Rep 2005;13:837-46.PubMed
34.
go back to reference Chen G, He C, Li L, et al. Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignant and malignant lesions of the cervix. BMC Cancer 2013;13:249.CrossRef Chen G, He C, Li L, et al. Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignant and malignant lesions of the cervix. BMC Cancer 2013;13:249.CrossRef
35.
go back to reference Riches K, Angelini TG, Mudhar GS, et al. Exploring smooth muscle phenotype and function in a bioreactor model of abdominal aortic aneurysm. J Transl Med 2013;11:208.CrossRef Riches K, Angelini TG, Mudhar GS, et al. Exploring smooth muscle phenotype and function in a bioreactor model of abdominal aortic aneurysm. J Transl Med 2013;11:208.CrossRef
36.
go back to reference Riches K, Clark E, Helliwell RJ, et al. Progressive development of aberrant smooth muscle cell phenotype in abdominal aortic aneurysm disease. J Vasc Res 2018;55:35-46.CrossRef Riches K, Clark E, Helliwell RJ, et al. Progressive development of aberrant smooth muscle cell phenotype in abdominal aortic aneurysm disease. J Vasc Res 2018;55:35-46.CrossRef
37.
go back to reference Jibawi A, Ahmed I, El-Sakka K, Yusuf SW. Management of concomitant cancer and abdominal aortic aneurysm. Cardiol Res Pract 2011;2011:516146.CrossRef Jibawi A, Ahmed I, El-Sakka K, Yusuf SW. Management of concomitant cancer and abdominal aortic aneurysm. Cardiol Res Pract 2011;2011:516146.CrossRef
38.
go back to reference Cao RY, Amand T, Ford MD, Piomelli U, Funk CD. The murine angiotensin II-induced abdominal aortic aneurysm model: Rupture risk and inflammatory progression patterns. Front Pharmacol 2010;1:9.PubMedPubMedCentral Cao RY, Amand T, Ford MD, Piomelli U, Funk CD. The murine angiotensin II-induced abdominal aortic aneurysm model: Rupture risk and inflammatory progression patterns. Front Pharmacol 2010;1:9.PubMedPubMedCentral
Metadata
Title
Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm
Authors
Richa Gandhi, MSc
Christopher Cawthorne, PhD
Lucinda J. L. Craggs, PhD
John D. Wright, MSc
Juozas Domarkas, PhD
Ping He, PhD
Joanna Koch-Paszkowski, MSc
Michael Shires
Andrew F. Scarsbrook, BMBS
Stephen J. Archibald, PhD
Charalampos Tsoumpas, PhD
Marc A. Bailey, MB, ChB, PhD
Publication date
01-10-2021
Publisher
Springer International Publishing
Published in
Journal of Nuclear Cardiology / Issue 5/2021
Print ISSN: 1071-3581
Electronic ISSN: 1532-6551
DOI
https://doi.org/10.1007/s12350-019-01946-y

Other articles of this Issue 5/2021

Journal of Nuclear Cardiology 5/2021 Go to the issue