Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study
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 radiot...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Cancer Imaging |
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| Online Access: | https://doi.org/10.1186/s40644-024-00685-9 |
| _version_ | 1797247090843189248 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Keith Wan Hang Chiu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T19:53:10Z |
| format | Article |
| id | doaj.art-c4a0289b76a641868eb295da7274bebe |
| institution | Directory Open Access Journal |
| issn | 1470-7330 |
| language | English |
| last_indexed | 2024-04-24T19:53:10Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Imaging |
| spelling | doaj.art-c4a0289b76a641868eb295da7274bebe2024-03-24T12:32:21ZengBMCCancer Imaging1470-73302024-03-0124111010.1186/s40644-024-00685-9Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed studyKeith Wan Hang Chiu0Kel Vin Tan1Xinxiang Yang2Xiaoqiang Zhu3Jingjing Shi4Chi-Leung Chiang5Lawrence Chan6Yuan Hui7Pek-Lan Khong8Kwan Man9Jason Wing Hon Wong10Department of Radiology and Imaging, Queen Elizabeth HospitalDepartment of Oncology, MRC Oxford Institute for Radiation Oncology, University of OxfordDepartment of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong KongDepartment of Diagnostic Radiology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong KongDepartment of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong KongDepartment of Health Technology and Informatics, The Hong Kong Polytechnic UniversityGuangdong Provincial People’s Hospital, Guangdong Academy of Medical ScienceClinical Imaging Research Center (CIRC), Yong Loo Lin School of Medicine, National University of SingaporeDepartment of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong KongAbstract 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.https://doi.org/10.1186/s40644-024-00685-9Hepatocellular carcinomaHypoxiaPET imagingRNA sequencing[11C]-acetate |
| spellingShingle | 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 Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study Cancer Imaging Hepatocellular carcinoma Hypoxia PET imaging RNA sequencing [11C]-acetate |
| title | Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study |
| title_full | Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study |
| title_fullStr | Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study |
| title_full_unstemmed | Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study |
| title_short | Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma – a bench to bed study |
| title_sort | prognostic pet 11c acetate uptake is associated with hypoxia gene expression in patients with late stage hepatocellular carcinoma a bench to bed study |
| topic | Hepatocellular carcinoma Hypoxia PET imaging RNA sequencing [11C]-acetate |
| url | https://doi.org/10.1186/s40644-024-00685-9 |
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