Longitudinal multi-tracer imaging of hepatocellular carcinoma identifies novel stage- and oncogene-specific changes

IF 3.6 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2025-02-16 DOI:10.1016/j.nucmedbio.2025.109000

Mari Teuter , Yuhai Hu , Tobias L. Ross , Kelsey Lolatte , Michael Ott , Frank M. Bengel , Asha Balakrishnan , Jens P. Bankstahl

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Abstract

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, globally. There is a need for novel biomarkers for early detection and novel, effective targeted therapies. Molecular imaging can faithfully visualize, characterize and quantify specific relevant biological processes.

Basic procedure

We performed longitudinal dedicated small-animal positron emission tomography–computed tomography (PET/CT) imaging to analyze changes in glucose metabolism using [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), amino acid turnover with [¹⁸F]fluoroethyltyrosine ([¹⁸F]FET), and chemokine receptor expression using [⁶⁸Ga]pentixafor targeting CXCR4, during stages of early tumor development, overt HCC and regression. We used two conditional transgenic mouse models of HCC, driven by clinically relevant oncogenes c-MYC (LT2/MYC) or HRASV12 (LT2/RAS). Conditional doxycycline-regulated mouse models, enable liver-specific oncogene activation or inhibition, leading to liver tumor development and regression, respectively. Correlation of our PET/CT findings with our gene expression and metabolomics data and with histological analyses followed.

Main findings

We show PET/CT identifies HCC stage-specific and oncogene-specific molecular changes that may serve as potential novel biomarkers and therapeutic targets. Glucose metabolism and CXCR4 chemokine expression are differentially deregulated during HCC development in an oncogene-specific manner. Our [¹⁸F]FDG results correlated with glucose transporter GLUT1 gene expression and with our metabolomics data. Increased expression of CXCR4 and CD68 inflammatory markers mirrored [⁶⁸Ga]pentixafor results in LT2/MYC mice. FET-based measurement of amino acid turnover are insensitive to stages of HCC-development, in our studies. Concurrently, no significant changes in expression of tyrosine metabolism genes were observed.

Principal conclusions

Our study highlights that identified changes in targeted molecular imaging can facilitate a better understanding of underlying biological processes and may help guide novel oncogene-specific targeted anti-tumor therapies in HCC, with promising translational potential.

Abstract Image

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肝细胞癌的纵向多示踪成像识别新的分期和癌基因特异性变化

背景：肝细胞癌（HCC）是全球癌症相关死亡的主要原因。需要新的生物标记物来进行早期检测和新的、有效的靶向治疗。分子成像可以真实地可视化、表征和量化特定的相关生物过程。我们采用纵向专用小动物正电子发射断层扫描-计算机断层扫描（PET/CT）成像，分析在肿瘤早期发展、HCC和消退阶段，[18F]氟脱氧葡萄糖（[18F]FDG）、[18F]氟乙基酪氨酸（[18F]FET）的糖代谢变化、[18F]氟乙基酪氨酸（[18F]FET）的氨基酸转换和[68Ga]替替沙靶向CXCR4的趋化因子受体表达。我们使用了两种条件转基因小鼠肝癌模型，由临床相关癌基因c-MYC （LT2/MYC）或HRASV12 （LT2/RAS）驱动。条件多西环素调节的小鼠模型，使肝脏特异性癌基因激活或抑制，分别导致肝脏肿瘤的发展和消退。我们的PET/CT结果与我们的基因表达和代谢组学数据以及组织学分析相关。我们发现PET/CT识别HCC分期特异性和癌基因特异性分子变化，可能作为潜在的新型生物标志物和治疗靶点。在HCC的发展过程中，糖代谢和CXCR4趋化因子的表达以癌基因特异性的方式被差异地解除调控。我们的[18F]FDG结果与葡萄糖转运体GLUT1基因表达和代谢组学数据相关。在LT2/MYC小鼠中，CXCR4和CD68炎症标志物的表达增加反映了[68Ga]pentixafor的结果。在我们的研究中，基于fet的氨基酸周转测量对hcc的发展阶段不敏感。同时，酪氨酸代谢基因的表达没有明显变化。我们的研究强调了靶向分子成像的变化可以促进更好地理解潜在的生物学过程，并可能有助于指导新的癌基因特异性靶向抗肿瘤治疗，具有很好的转化潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.