将 Fn14 作为恶病质的治疗靶点可重新编程小鼠肿瘤和大脑中的糖酵解途径。
Targeting Fn14 as a therapeutic target for cachexia reprograms the glycolytic pathway in tumour and brain in mice.
发表日期：2024 Jul 26
作者：
Ingrid Julienne Georgette Burvenich, Laura Danielle Osellame, Angela Rigopoulos, Nhi Huynh, Zhipeng Cao, Nicholas Johannes Hoogenraad, Andrew Mark Scott
来源：
Eur J Nucl Med Mol I
摘要：
恶病质是一种复杂的综合征，其特征是无意的体重减轻、进行性肌肉萎缩和食欲不振。抗 Fn14 抗体 (mAb 002) 以癌症恶病质小鼠模型中的 TWEAK 受体 (Fn14) 为目标，可以通过恢复小鼠体重来延长小鼠的寿命。在这里，我们通过 [18F]FDG PET 成像研究了恶病质小鼠模型中的葡萄糖代谢变化，以探讨 Fn14 是否在癌症恶病质期间发生的代谢变化中发挥作用。 [18F]FDG PET/MRI 成像在恶病质中进行诱导肿瘤模型与不诱导恶病质的模型。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 SUV 平均值。[18F]FDG PET 成像表明，与非恶病质肿瘤小鼠相比，恶病质小鼠的肿瘤和大脑摄取增加。 mAb 002 治疗能够减少肿瘤中的 [18F]FDG 摄取（P < 0.05，n = 3）。 Fn14 KO 肿瘤不会引起体重减轻，并且 [18F]FDG 肿瘤和脑摄取也不会随着时间的推移而增加。在携带 Fn14 KO 肿瘤的非恶病质小鼠中，[18F]FDG 肿瘤摄取显着低于携带 Fn14 WT 对应恶病质小鼠（P<0.01）。作为葡萄糖代谢的副产品，在表达 Fn14 的恶病质诱导肿瘤中，L-乳酸的产生也有所增加。我们的结果表明，Fn14 受体激活与恶病质诱导肿瘤的葡萄糖代谢有关。© 2024。作者。
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.[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.[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.Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours.© 2024. The Author(s).