Targeting Fn14 as a therapeutic target for cachexia reprograms the glycolytic pathway in tumour and brain in mice.

IF 8.6 1区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Ingrid Julienne Georgette Burvenich, Laura Danielle Osellame, Angela Rigopoulos, Nhi Huynh, Zhipeng Cao, Nicholas Johannes Hoogenraad, Andrew Mark Scott
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Abstract

Purpose: Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [18F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia.

Methods: [18F]FDG PET/MRI imaging was performed in cachexia-inducing tumour models versus models that do not induce cachexia. SUVaverage was calculated for all tumours via volume of interest (VOI) analysis of PET/MRI overlay images using PMOD software.

Results: [18F]FDG PET imaging demonstrated increased tumour and brain uptake in cachectic versus non-cachectic tumour-bearing mice. Therapy with mAb 002 was able to reduce [18F]FDG uptake in tumours (P < 0.05, n = 3). Fn14 KO tumours did not induce body weight loss and did not show an increase in [18F]FDG tumour and brain uptake over time. In non-cachectic mice bearing Fn14 KO tumours, [18F]FDG tumour uptake was significantly lower (P < 0.01) than in cachectic mice bearing Fn14 WT counterparts. As a by-product of glucose metabolism, l-lactate production was also increased in cachexia-inducing tumours expressing Fn14.

Conclusion: Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours.

Abstract Image

将 Fn14 作为恶病质的治疗靶点,可重新规划小鼠肿瘤和大脑中的糖酵解途径。
目的:恶病质是一种复杂的综合征,其特点是无意中体重减轻、进行性肌肉萎缩和食欲不振。抗 Fn14 抗体(mAb 002)在癌症恶病质小鼠模型中靶向 TWEAK 受体(Fn14),可通过恢复小鼠体重延长小鼠寿命。在此,我们通过[18F]FDG PET成像研究了小鼠恶病质模型中葡萄糖代谢的变化,以探讨Fn14是否在癌症恶病质过程中发生的代谢变化中发挥作用。方法:在诱导恶病质的肿瘤模型和不诱导恶病质的模型中进行[18F]FDG PET/MRI成像。使用 PMOD 软件对 PET/MRI 叠加图像进行感兴趣体积(VOI)分析,计算所有肿瘤的 SUVaverage:结果:[18F]FDG PET 成像显示,罹患恶性肿瘤的小鼠与未罹患恶性肿瘤的小鼠相比,肿瘤和大脑摄取量增加。使用 mAb 002 治疗能够降低肿瘤的[18F]FDG 摄取量(P 18F]FDG 肿瘤和脑摄取量随时间变化)。在携带 Fn14 KO 肿瘤的非冷冻小鼠中,[18F]FDG 肿瘤摄取量显著降低(P 结论:Fn14 KO 小鼠的[18F]FDG 肿瘤摄取量显著低于冷冻小鼠:我们的研究结果表明,Fn14 受体的激活与恶病质诱导肿瘤的葡萄糖代谢有关。
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来源期刊
CiteScore
15.60
自引率
9.90%
发文量
392
审稿时长
3 months
期刊介绍: The European Journal of Nuclear Medicine and Molecular Imaging serves as a platform for the exchange of clinical and scientific information within nuclear medicine and related professions. It welcomes international submissions from professionals involved in the functional, metabolic, and molecular investigation of diseases. The journal's coverage spans physics, dosimetry, radiation biology, radiochemistry, and pharmacy, providing high-quality peer review by experts in the field. Known for highly cited and downloaded articles, it ensures global visibility for research work and is part of the EJNMMI journal family.
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