Physiologic and molecular characterization of a novel murine model of metastatic head and neck cancer cachexia.
Physiologic and molecular characterization of a novel murine model of metastatic head and neck cancer cachexia.
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DOI：
10.1002/jcsm.12745
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Marks DL
中科院分区：
文献类型：
--
作者：
Olson B;Norgard MA;Levasseur PR;Zhu X;Marks DL
癌症恶病质是一种代谢紊乱，其特征是脂肪和瘦肉逐渐减少，导致显著的消瘦，最终导致生活质量下降和死亡率增加。目前缺乏针对恶病质的有效治疗方法，这可能是由于临床相关的恶病质模型不匹配。具体来说，在临床环境中观察到的恶病质通常与转移的晚期或晚期癌症相关，但恶病质的临床前转移模型有限。此外，头颈癌患者中恶病质的患病率很高，但很少有头颈癌恶病质的临床前模型。除了这些缺点外，恶病质在任何一种癌症中也具有异质性，而具有相似疾病负担的患者可能会出现明显不同程度的恶病质症状。为了解决这些问题，我们描述了人类乳头瘤病毒（HPV）阳性头颈部鳞状细胞癌的转移模型，该模型概括了癌症恶病质的主要临床和分子特征。将经HPV16、E6、E7及hRas、荧光素酶（mEERL）稳定转化并转移至肺（MLM）的口咽鳞状细胞癌细胞皮下植入雄性和雌性C57BL/6小鼠。然后，我们在两个MLM亚克隆中对肿瘤发展过程中的生理、行为和分子特征进行了强有力的表征。注射了MLM肿瘤细胞的小鼠迅速发展为原发性肿瘤，并最终转移到肺部。尽管没有厌食症，但在肿瘤发展过程中，MLM3（而非MLM5）移植小鼠的脂肪和瘦肉质量逐渐下降（P < 0.05）。在行为学上，植入MLM3的小鼠表现出运动行为减少和筑巢受损（P < 0.05）。观察到与恶病质相关的肌肉分解代谢程序，包括E3泛素连接酶和自噬上调，以及进行性脂肪消耗和伴随的褐变基因特征。肿瘤进展还与下丘脑和外周器官炎症以及中性粒细胞与淋巴细胞比值升高相关（P < 0.05）。最后，我们描述了自主轮跑对MLM3恶病质的脂肪和瘦肉质量节约效果（P < 0.05）。这种转移性癌症恶病质的同基因MLM3同种异体移植模型是可靠的、一致的，并且很容易概括癌症恶病质的关键临床和分子特征以及异质性。由于恶病质的转移模型很少存在，尽管恶病质经常伴随着转移进展，我们相信该模型更准确地捕捉了在临床环境中观察到的癌症恶病质，因此非常适合未来的机制研究和这种致残性代谢紊乱的临床前治疗开发。
Cancer cachexia is a metabolic disorder characterized by the progressive loss of fat and lean mass that results in significant wasting, ultimately leading to reduced quality of life and increased mortality. Effective therapies for cachexia are lacking, potentially owing to the mismatch in clinically relevant models of cachexia. Specifically, cachexia observed in a clinical setting is commonly associated with advanced or late‐stage cancers that are metastatic, yet pre‐clinical metastatic models of cachexia are limited. Furthermore, the prevalence of cachexia in head and neck cancer patients is high, yet few pre‐clinical models of head and neck cancer cachexia exist. In addition to these shortcomings, cachexia is also heterogeneous among any given cancer, whereas patients with similar disease burden may experience significantly different degrees of cachexia symptoms. In order to address these issues, we characterize a metastatic model of human papilloma virus (HPV) positive head and neck squamous cell carcinoma that recapitulates the cardinal clinical and molecular features of cancer cachexia. Male and female C57BL/6 mice were implanted subcutaneously with oropharyngeal squamous cell carcinoma cells stably transformed with HPV16 E6 and E7 together with hRas and luciferase (mEERL) that metastasizes to the lungs (MLM). We then robustly characterize the physiologic, behavioural, and molecular signatures during tumour development in two MLM subclones. Mice injected with MLM tumour cells rapidly developed primary tumours and eventual metastatic lesions to the lungs. MLM3, but not MLM5, engrafted mice progressively lost fat and lean mass during tumour development despite the absence of anorexia (P < 0.05). Behaviourally, MLM3‐implanted mice displayed decreased locomotor behaviours and impaired nest building (P < 0.05). Muscle catabolism programmes associated with cachexia, including E3 ubiquitin ligase and autophagy up‐regulation, along with progressive adipose wasting and accompanying browning gene signatures, were observed. Tumour progression also corresponded with hypothalamic and peripheral organ inflammation, as well as an elevation in neutrophil‐to‐lymphocyte ratio (P < 0.05). Finally, we characterize the fat and lean mass sparing effects of voluntary wheel running on MLM3 cachexia (P < 0.05). This syngeneic MLM3 allograft model of metastatic cancer cachexia is reliable, consistent, and readily recapitulates key clinical and molecular features and heterogeneity of cancer cachexia. Because few metastatic models of cachexia exist—even though cachexia often accompanies metastatic progression—we believe this model more accurately captures cancer cachexia observed in a clinical setting and thus is well suited for future mechanistic studies and pre‐clinical therapy development for this crippling metabolic disorder.
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DOI：
10.1084/jem.20111020
发表时间：
2011-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Braun TP;Zhu X;Szumowski M;Scott GD;Grossberg AJ;Levasseur PR;Graham K;Khan S;Damaraju S;Colmers WF;Baracos VE;Marks DL
通讯作者：
Marks DL
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DOI：
10.1523/jneurosci.2311-11.2011
发表时间：
2011-08-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Grossberg AJ;Zhu X;Leinninger GM;Levasseur PR;Braun TP;Myers MG Jr;Marks DL
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Marks DL
影响因子：
15.9
作者：
Acharyya, S;Ladner, KJ;Guttridge, DC
通讯作者：
Guttridge, DC
DOI：
10.1152/ajpregu.90318.2008
发表时间：
2008-12-01
影响因子：
2.8
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Frenette, Jerome
影响因子：
3.8
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Groenvold, Mogens;Petersen, Morten Aagaard;Mouridsen, Henning T.
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