Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study.
Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study.
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DOI：
10.1002/jcsm.12864
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Kim SY
中科院分区：
文献类型：
--
作者：
Luan Y;Zhang Y;Yu SY;You M;Xu PC;Chung S;Kurita T;Zhu J;Kim SY
癌症相关恶病质（CAC）是一种伴有代谢功能障碍的进行性肌肉萎缩和脂肪减少的复杂综合征，严重增加了癌症患者的发病率和死亡率。然而，由于CAC综合征的复杂性和缺乏模拟其分期进展的临床前模型，关注CAC进展的潜在机制的研究有限。我们描述了转基因雌性卵巢肿瘤小鼠CAC的发生和进展。我们测量了该小鼠模型血清（n = 6）中拟议的CAC生物标志物（激活素A、GDF15、IL‐6、IL‐1β和TNF‐α）。激活素A和GDF15的变化（n = 6）与体重随时间的下降有关。在CAC进展过程中评估肌肉萎缩（n≥6）和脂肪组织消耗（n≥7）的形态测量和信号标志物。本研究中使用的转基因小鼠模型的癌症相关恶病质症状模拟了人类CAC的进展，包括体重急剧下降、骨骼肌萎缩和脂肪组织消耗。两种恶病质生物标志物激活素A和GDF15的血清水平在恶病质进展过程中显著升高（分别为76倍和10倍）。通过上调肌肉特异性E3连接酶Atrogin‐1和Murf‐1（分别为16倍和14倍），骨骼肌中检测到蛋白水解活性的过度激活，肌肉纤维横截面积减少（P < 0.001）。与p - p38 MAPK、FOXO3和p - AMPKα相关的肌肉萎缩机制在血清激活素a升高的同时高度激活。在该小鼠模型中，脂肪量（n≥6）和白色脂肪细胞大小（n = 6）减少（p < 0.0001），也观察到显著的脂肪减少。脂肪组织的消耗以产热为基础，由解偶联蛋白1 （UCP1）的上调支持。脂肪组织纤维化也与脂肪组织损失同时发生（n≥13）（p < 0.0001）。我们的新型临床前CAC小鼠模型模拟人类CAC表型和血清生物标志物。本研究小鼠模型肌肉萎缩表现为蛋白水解，脂肪组织萎缩表现为褐变，血清活化素A和GDF15升高，胰腺和肝脏萎缩。该小鼠系将是帮助阐明CAC分子介质和解剖CAC进展过程中代谢功能障碍和组织萎缩的最佳临床前模型。
Cancer‐associated cachexia (CAC) is a complex syndrome of progressive muscle wasting and adipose loss with metabolic dysfunction, severely increasing the morbidity and mortality risk in cancer patients. However, there are limited studies focused on the underlying mechanisms of the progression of CAC due to the complexity of this syndrome and the lack of preclinical models that mimics its stagewise progression. We characterized the initiation and progression of CAC in transgenic female mice with ovarian tumours. We measured proposed CAC biomarkers (activin A, GDF15, IL‐6, IL‐1β, and TNF‐α) in sera (n = 6) of this mouse model. The changes of activin A and GDF15 (n = 6) were correlated with the decline of bodyweight over time. Morphometry and signalling markers of muscle atrophy (n ≥ 6) and adipose tissue wasting (n ≥ 7) were assessed during CAC progression. Cancer‐associated cachexia symptoms of the transgenic mice model used in this study mimic the progression of CAC seen in humans, including drastic body weight loss, skeletal muscle atrophy, and adipose tissue wasting. Serum levels of two cachexia biomarkers, activin A and GDF15, increased significantly during cachexia progression (76‐folds and 10‐folds, respectively). Overactivation of proteolytic activity was detected in skeletal muscle through up‐regulating muscle‐specific E3 ligases Atrogin‐1 and Murf‐1 (16‐folds and 14‐folds, respectively) with decreasing cross‐sectional area of muscle fibres (P < 0.001). Muscle wasting mechanisms related with p‐p38 MAPK, FOXO3, and p‐AMPKα were highly activated in concurrence with an elevation in serum activin A. Dramatic fat loss was also observed in this mouse model with decreased fat mass (n ≥ 6) and white adipocytes sizes (n = 6) (P < 0.0001). The adipose tissue wasting was based on thermogenesis, supported by the up‐regulation of uncoupling protein 1 (UCP1). Fibrosis in adipose tissue was also observed in concurrence with adipose tissue loss (n ≥ 13) (p < 0.0001). Our novel preclinical CAC mouse model mimics human CAC phenotypes and serum biomarkers. The mouse model in this study showed proteolysis in muscle atrophy, browning in adipose tissue wasting, elevation of serum activin A and GDF15, and atrophy of pancreas and liver. This mouse line would be the best preclinical model to aid in clarifying molecular mediators of CAC and dissecting metabolic dysfunction and tissue atrophy during the progression of CAC.
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影响因子：
82.9
作者：
Emmerson, Paul J.;Wang, Feng;Wu, Xinle
通讯作者：
Wu, Xinle
影响因子：
3.8
作者：
Judge SM;Wu CL;Beharry AW;Roberts BM;Ferreira LF;Kandarian SC;Judge AR
通讯作者：
Judge AR
PI3K在卵母细胞中的组成型激活诱导卵巢颗粒细胞肿瘤。
影响因子：
11.2
作者：
Kim SY;Ebbert K;Cordeiro MH;Romero MM;Whelan KA;Suarez AA;Woodruff TK;Kurita T
通讯作者：
Kurita T
影响因子：
8.9
作者：
Huang, Chueh-Yi;Yang, Yuh-Cheng;Lee, Jie
通讯作者：
Lee, Jie
DOI：
10.1073/pnas.91.19.8817
发表时间：
1994-09-13
影响因子：
11.1
作者：
MATZUK, MM;FINEGOLD, MJ;BRADLEY, A
通讯作者：
BRADLEY, A