Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Imaging
Published in: Cancer Imaging 1/2024

Open Access 01-12-2024 | Hepatocellular Carcinoma | Research article

Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study

Authors: Keith Wan Hang Chiu, Kel Vin Tan, Xinxiang Yang, Xiaoqiang Zhu, Jingjing Shi, Chi-Leung Chiang, Lawrence Chan, Yuan Hui, Pek-Lan Khong, Kwan Man, Jason Wing Hon Wong

Published in: Cancer Imaging | Issue 1/2024

Login to get access

Abstract

Background

Positron Emission Tomography (PET) with combined [18F]-FDG and [11C]-acetate (dual-tracer) is used for the management of hepatocellular carcinoma (HCC) patients, although its prognostic value and underlying molecular mechanism remain poorly understood. We hypothesized that radiotracer uptake might be associated with tumor hypoxia and validated our findings in public and local human HCC cohorts.

Methods

Twelve orthotopic HCC xenografts were established using MHCC97L cells in female nude mice, with 5 having undergone hepatic artery ligation (HAL) to create tumor hypoxia in vivo. Tumors in both Control and HAL-treated xenografts were imaged with [11C]-acetate and [18F]-FDG PET-MR and RNA sequencing was performed on the resected tumors. Semiquantitative analysis of PET findings was then performed, and the findings were then validated on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and patients from our institution.

Results

HAL-treated mice showed lower [11C]-acetate (HAL-treated vs. Control, tumor-to-liver SUV ratio (SUVTLR): 2.14[2.05–2.21] vs 3.11[2.75–5.43], p = 0.02) but not [18F]-FDG (HAL-treated vs. Control, SUVTLR: 3.73[3.12–4.35] vs 3.86[3.7–5.29], p = 0.83) tumor uptakes. Gene expression analysis showed the PET phenotype is associated with upregulation of hallmark hypoxia signature. The prognostic value of the hypoxia gene signature was tested on the TCGA-LIHC cohort with upregulation of hypoxia gene signature associated with poorer overall survival (OS) in late-stage (stage III and IV) HCC patients (n = 66, OS 2.05 vs 1.67 years, p = 0.046). Using a local cohort of late-stage HCC patients who underwent dual-tracer PET-CT, tumors without [11C]-acetate uptake are associated with poorer prognosis (n = 51, OS 0.25 versus 1.21 years, p < 0.0001) and multivariable analyses showed [11C]-acetate tumor uptake as an independent predictor of OS (HR 0.17 95%C 0.06–0.42, p < 0.0001).

Conclusions

[11C]-acetate uptake is associated with alteration of tumor hypoxia gene expression and poorer prognosis in patients with advanced HCC.
Appendix
Available only for authorised users
Literature
1.
Altekruse SF, McGlynn KA, Dickie LA, Kleiner DE. Hepatocellular Carcinoma Confirmation, Treatment, and Survival in Surveillance, Epidemiology, and End Results Registries, 1992–2008. Hepatology. 2012;55(2):476–82.CrossRefPubMed
2.
Kitisin K, Packiam V, Steel J, Humar A, Gamblin TC, Geller DA, et al. Presentation and outcomes of hepatocellular carcinoma patients at a western centre. HPB. 2011;13(10):712–22.CrossRefPubMedPubMedCentral
3.
4.
Tommaso LD, Spadaccini M, Donadon M, Personeni N, Elamin A, Aghemo A, et al. Role of liver biopsy in hepatocellular carcinoma. World J Gastroenterol. 2019;25(40):6041–52.CrossRefPubMedPubMedCentral
5.
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nature Reviews Disease Primers. 2021;7(1):6.
6.
Ho CL, Yu SC, Yeung DW. 11C-acetate PET imaging in hepatocellular carcinoma and other liver masses. J Nucl Med. 2003;44(2):213–21.PubMed
7.
Park S, Kim T-S, Kang SH, Kim HB, Park J-W, Kim S-k. 11C-acetate and 18F-fluorodeoxyglucose positron emission tomography/computed tomography dual imaging for the prediction of response and prognosis after transarterial chemoembolization. Medicine. 2018;97(37):e12311.CrossRefPubMedPubMedCentral
8.
Larsson P, Arvidsson D, Bjornstedt M, Isaksson B, Jersenius U, Motarjemi H, et al. Adding 11C-acetate to 18F-FDG at PET Examination Has an Incremental Value in the Diagnosis of Hepatocellular Carcinoma. Mol Imaging Radionucl Ther. 2012;21(1):6–12.CrossRefPubMedPubMedCentral
9.
Park J-W, Kim JH, Kim SK, Kang KW, Park KW, Choi J-I, et al. A Prospective Evaluation of 18F-FDG and 11C-Acetate PET/CT for Detection of Primary and Metastatic Hepatocellular Carcinoma. J Nucl Med. 2008;49(12):1912–21.CrossRefPubMed
10.
Gao X, Lin S-H, Ren F, Li J-T, Chen J-J, Yao C-B, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun. 2016;7(1):11960.CrossRefPubMedPubMedCentral
11.
Yang X, Yeung WHO, Tan KV, Ng TPK, Pang Li, Zhou J, et al. Development of cisplatin-loaded hydrogels for trans-portal vein chemoembolization in an orthotopic liver cancer mouse model. Drug Delivery. 2021;28(1):520–9.CrossRefPubMedPubMedCentral
12.
13.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013;30(7):923–30.CrossRefPubMed
14.
15.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
16.
Goldman MJ, Craft B, Hastie M, Repečka K, McDade F, Kamath A, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020;38(6):675–8.CrossRefPubMedPubMedCentral
17.
Tan P, Hoshida Y. Nearest Template Prediction: A Single-Sample-Based Flexible Class Prediction with Confidence Assessment. PLoS ONE. 2010;5(11):e15543.CrossRef
18.
19.
Lu R-C, She B, Gao W-T, Ji Y-H, Xu D-D, Wang Q-S, et al. Positron-emission tomography for hepatocellular carcinoma: Current status and future prospects. World J Gastroenterol. 2019;25(32):4682–95.CrossRefPubMedPubMedCentral
20.
Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004;23(9):1949–56.CrossRefPubMedPubMedCentral
21.
22.
Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM. Concordant Regulation of Gene Expression by Hypoxia and 2-Oxoglutarate-dependent Dioxygenase Inhibition. J Biol Chem. 2006;281(22):15215–26.CrossRefPubMed
23.
van der Pol CB, Lim CS, Sirlin CB, McGrath TA, Salameh J-P, Bashir MR, et al. Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy—A Systematic Review. Gastroenterology. 2019;156(4):976–86.CrossRefPubMed
24.
Erickson B, Kirk S, Lee Y, Bathe O, Kearns M, Gerdes C, et al. Radiology data from the cancer genome atlas liver hepatocellular carcinoma [TCGA-LIHC] collection. The Cancer Imaging Archive. 2016.
25.
Singh PK, Heiden BT, Chen G, Hermann M, Brown RKJ, Orringer MB, et al. 18F-FDG PET intensity correlates with a hypoxic gene signature and other oncogenic abnormalities in operable non-small cell lung cancer. Plos One. 2018;13(7):e0199970.CrossRef
26.
Yun M, Bang S-H, Kim JW, Park JY, Kim KS, Lee JD. The Importance of Acetyl Coenzyme A Synthetase for 11C-Acetate Uptake and Cell Survival in Hepatocellular Carcinoma. J Nucl Med. 2009;50(8):1222–8.CrossRefPubMed
27.
Xia H, Chen J, Gao H, Kong SN, Deivasigamani A, Shi M, et al. Hypoxia-induced modulation of glucose transporter expression impacts 18F-fluorodeoxyglucose PET-CT imaging in hepatocellular carcinoma. Eur J Nucl Med Mol Imaging. 2019;47(4):787–97.CrossRefPubMed
28.
29.
Zhao J-G, Feng G-S, Kong X-Q, Li X, Li M-H, Cheng Y-S. Assessment of hepatocellular carcinoma vascularity before and after transcatheter arterial chemoembolization by using first pass perfusion weighted MR imaging. World J Gastroenterol. 2004;10(8):1152–6.CrossRefPubMedPubMedCentral
30.
van den Hoff J, Burchert W, Borner AR, Fricke H, Kuhnel G, Meyer GJ, et al. [1-(11)C]Acetate as a quantitative perfusion tracer in myocardial PET. J Nucl Med. 2001;42(8):1174–82.PubMed
31.
Liu Z, Tu K, Wang Y, Yao B, Li Q, Wang L, et al. Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling. Cell Physiol Biochem. 2017;44(5):1856–68.CrossRefPubMed
32.
Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022;76(3):681–93.CrossRefPubMed
33.
Lopci E, Grassi I, Chiti A, Nanni C, Cicoria G, Toschi L, et al. PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence. Am J Nucl Med Mol Imaging. 2014;4(4):365–84.PubMedPubMedCentral
34.
Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–50.CrossRefPubMed
Metadata
Title
Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study
Authors
Keith Wan Hang Chiu
Kel Vin Tan
Xinxiang Yang
Xiaoqiang Zhu
Jingjing Shi
Chi-Leung Chiang
Lawrence Chan
Yuan Hui
Pek-Lan Khong
Kwan Man
Jason Wing Hon Wong
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Cancer Imaging / Issue 1/2024
Electronic ISSN: 1470-7330
DOI
https://doi.org/10.1186/s40644-024-00685-9

Other articles of this Issue 1/2024

Cancer Imaging 1/2024 Go to the issue

Research article

Impact of deep learning image reconstruction on volumetric accuracy and image quality of pulmonary nodules with different morphologies in low-dose CT

Research article

Head-to-head comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT for the evaluation of tonsil cancer and lymph node metastases: a single-centre retrospective study

Research article

[89Zr]Zr-PSMA-617 PET/CT characterization of indeterminate [68Ga]Ga-PSMA-11 PET/CT findings in patients with biochemical recurrence of prostate cancer: lesion-based analysis

Research article

Multi-institutional validation of a radiomics signature for identification of postoperative progression of soft tissue sarcoma

Review

Artificial intelligence-based MRI radiomics and radiogenomics in glioma

Research article

Superiority of 18F-FAPI-42 PET/CT in the detection of primary tumor and management of appendiceal neoplasm to 18F-FDG PET/CT and CE-CT
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits