Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia.
Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia.
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DOI：
10.1002/jcsm.12311
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Bonetto A
中科院分区：
文献类型：
--
作者：
Pin F;Barreto R;Kitase Y;Mitra S;Erne CE;Novinger LJ;Zimmers TA;Couch ME;Bonewald LF;Bonetto A
恶病质经常发生在晚期卵巢癌（OC）的妇女中，沿着增强的炎症。尽管恶病质占所有癌症死亡的三分之一，但由于临床前动物模型数量有限，恶病质通常在OC中进行研究。我们的目的是通过描述OC小鼠模型的恶病质表型来解决这一问题。向Nod SCID γ小鼠（n = 6-10）腹膜内注射1 × 107 ES-2人OC细胞，以模拟播散性腹部疾病。肌肉大小和力量，以及骨形态，进行了评估。在C2 C12肌管培养物中研究了肿瘤对肌纤维的影响。在肿瘤宿主的血清和腹水以及肿瘤切片中检测IL-6水平。在大约2周内，ES-2细胞发展成腹部肿瘤，浸润网膜、肠系膜和邻近器官。ES-2肿瘤引起严重的恶病质，伴有体重显著减轻（-12%，P < 0.01）和腹腔内腹水积聚（4.7 ± 1.5 mL）。荷瘤小鼠的骨骼肌明显较小（约-35%，P < 0.001）。肌肉损失伴随纤维萎缩，与肌肉横截面积减少（-34%，P < 0.01）和肌肉无力（-50%，P < 0.001）一致。通过双能X线吸收测定法进行的身体成分评估显示骨密度（-8%，P < 0.01）和骨矿物质含量（-19%，P < 0.01）降低，也与股骨和椎骨的骨小梁减少一致，如骨形态测定的微CT成像所示。在ES-2小鼠模型中，恶病质也与血浆和腹水中高肿瘤源性IL-6水平相关（分别为26.3和279.6 pg/mL）和磷酸化STAT 3升高（+274%，P < 0.001），磷酸化AKT降低（-44%，P < 0.001）和线粒体蛋白减少，以及蛋白质泛素化（+42%，P < 0.001）和肿瘤宿主骨骼肌中泛素连接酶的表达增加。类似地，ES-2条件培养基直接诱导C2 C12小鼠肌管中的纤维萎缩（-16%，P < 0.001），与升高的磷酸化STAT 3（+1.4倍，P < 0.001）和改变的线粒体体内平衡和代谢一致，而通过INCB 018424抑制IL-6/STAT 3信号传导足以恢复肌管大小。我们的研究结果表明，ES-2 OC的发展促进了体内和体外条件下的肌肉萎缩，伴随着骨量丢失，肌肉蛋白catalysis增强，线粒体稳态异常和IL-6水平升高。因此，这代表了一个适当的模型，OC恶病质的研究。我们的模型将有助于确定分子介质，可以有效地针对，以改善与OC相关的肌肉萎缩。
Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under‐studied in OC due to a limited number of pre‐clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. Nod SCID gamma mice (n = 6–10) were injected intraperitoneally with 1 × 107 ES‐2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour‐derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL‐6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. In about 2 weeks, ES‐2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES‐2 tumours caused severe cachexia with marked loss of body weight (–12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour‐bearing mice (approximately –35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross‐sectional area (–34%, P < 0.01) and muscle weakness (–50%, P < 0.001). Body composition assessment by dual‐energy X‐ray absorptiometry revealed decreased bone mineral density (–8%, P < 0.01) and bone mineral content (–19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro‐CT imaging of bone morphometry. In the ES‐2 mouse model, cachexia was also associated with high tumour‐derived IL‐6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho‐STAT3 (+274%, P < 0.001), reduced phospho‐AKT (–44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES‐2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (–16%, P < 0.001), consistent with elevated phospho‐STAT3 (+1.4‐fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL‐6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. Our results suggest that the development of ES‐2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL‐6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
3.7
作者：
Fakkert IE;van der Veer E;Abma EM;Lefrandt JD;Wolffenbuttel BH;Oosterwijk JC;Slart RH;Westrik IG;de Bock GH;Mourits MJ
通讯作者：
Mourits MJ
影响因子：
--
作者：
De Benedetti, Fabrizio;Rucci, Nadia;Teti, Anna
通讯作者：
Teti, Anna
影响因子：
7.2
作者：
Gershenson, David M.;Sun, Charlotte C.;Bodurka, Diane C.
通讯作者：
Bodurka, Diane C.
DOI：
10.1097/01.mco.0000078983.18774.cc
发表时间：
2003-07-01
影响因子：
3.1
作者：
Argilés, JM;Busquets, S;López-Soriano, FJ
通讯作者：
López-Soriano, FJ