Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice.
Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice.
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DOI：
10.1002/jcsm.12346
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Jackman RW
中科院分区：
文献类型：
--
作者：
Kandarian SC;Nosacka RL;Delitto AE;Judge AR;Judge SM;Ganey JD;Moreira JD;Jackman RW
癌症恶病质是一种代谢消耗综合征，与不良预后密切相关。导致脂肪和肌肉损失的起始因素在很大程度上尚不清楚。此前，我们发现 C26 结肠癌细胞分泌的白血病抑制因子 (LIF) 是导致治疗后肌管萎缩的原因。在本研究中，我们通过敲除 C26 细胞中的 Lif 来测试 C26 肿瘤来源的 LIF 是否是小鼠癌症恶病质所必需的。使用 CRISPR-Cas9 制备了 C26 Lif 无效肿瘤细胞系。比较了接种 C26 与 C26Lif−/− 肿瘤细胞的小鼠的恶病质测量结果，并比较了用 C26 与 C26Lif−/− 肿瘤细胞的培养基处理的肌管的萎缩情况。比较了携带 C26 与 C26Lif−/− 肿瘤的小鼠血清中以及来自这些肿瘤细胞系的培养基中的 25 种细胞因子/趋化因子的水平。在研究终点，C26 小鼠表现出疾病的外在迹象，而患有 C26Lif−/− 肿瘤的小鼠则显得健康。与患有 C26 肿瘤的小鼠相比，患有 C26Lif−/− 肿瘤的小鼠体重减轻、肌肉减少、脂肪减少和脾肿大改善了 55–75%（P < 0.05）。心脏不受 LIF 水平的影响，因为 C26 和 C26Lif−/− 荷瘤小鼠的心脏质量损失相同。小鼠血清中的 LIF 水平完全取决于肿瘤细胞的分泌。在 C26 小鼠中，IL-6 和 G-CSF 的血清水平分别增加了 79 倍和 68 倍，但在 C26Lif−/− 小鼠中仅分别增加了 5 倍和 2 倍，这表明 IL-6 和 G-CSF 的增加依赖于肿瘤源性 LIF。这项研究首次使用 CRISPR-Cas9 敲除肿瘤细胞中的候选恶病质因子。该结果为LIF作为体内C26肿瘤的主要恶病质启动因素提供了直接证据。肿瘤源性 LIF 也是 C26 肿瘤细胞和 C26 荷瘤小鼠中多种细胞因子的调节剂。启动恶病质过程的肿瘤衍生因子（例如 LIF）的鉴定可立即应用于治疗恶病质的疗法的开发。这是研究的原理证明，当在人体细胞中进行时，将使以患者特异性的方式了解导致恶病质的因素成为可能。
Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour‐derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells. A C26 Lif null tumour cell line was made using CRISPR‐Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26Lif−/− tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26Lif−/− tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26Lif−/− tumours and in the medium from these tumour cell lines. At study endpoint, C26 mice showed outward signs of sickness while mice with C26Lif−/− tumours appeared healthy. Mice with C26Lif−/− tumours showed a 55–75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C26Lif−/− tumour‐bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin‐6 and G‐CSF were increased by 79‐fold and 68‐fold, respectively, in C26 mice but only by five‐fold and two‐fold, respectively, in C26Lif−/− mice, suggesting that interleukin‐6 and G‐CSF increases are dependent on tumour‐derived LIF. This study shows the first use of CRISPR‐Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour‐derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour‐bearing mice. The identification of tumour‐derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient‐specific manner.
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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
基于炎症的癌症恶病质调节。
影响因子：
--
作者：
Onesti JK;Guttridge DC
通讯作者：
Guttridge DC
影响因子：
3.8
作者：
Delitto, Daniel;Judge, Sarah M.;Trevino, Jose G.
通讯作者：
Trevino, Jose G.
影响因子：
30.8
作者：
Ben-David U;Ha G;Tseng YY;Greenwald NF;Oh C;Shih J;McFarland JM;Wong B;Boehm JS;Beroukhim R;Golub TR
通讯作者：
Golub TR
DOI：
10.1016/j.bbamcr.2004.11.002
发表时间：
2005-04-15
影响因子：
5.1
作者：
Jo, C;Kim, H;Jo, SA
通讯作者：
Jo, SA