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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >MAP3K11/GDF15 axis is a critical driver of cancer cachexia
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MAP3K11/GDF15 axis is a critical driver of cancer cachexia

机译：MAP3K11 / GDF15轴是癌症恶病质的关键驱动因素

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Abstract Background Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. Methods Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. Results Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. Conclusions The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome.
机译：摘要背景癌症相关的恶病质在疾病过程中会影响大多数癌症患者，并被认为直接导致所有癌症死亡的四分之一。目前的证据表明，促炎症状态可能与该综合征有关，尽管对恶病质发展的分子机制了解甚少。这项工作的目的是确定癌症恶病质的关键驱动因素，可以为该综合征的治疗和/或预防提供潜在的干预点。方法采用基因工程和异种移植肿瘤模型剖析驱动癌症恶病质的分子机制。从恶病质和非恶病质癌症患者和小鼠模型的血浆中进行细胞因子分析，以将循环细胞因子水平与恶病质表型相关联。结果利用工程化的肿瘤模型，我们确定了MAP3K11 / GDF15途径激活是癌症恶病质的有效诱因。 GDF15的表达增加和高循环水平是该过程的关键介体。在动物模型中，肿瘤产生的GDF15足以触发恶病质表型。在动物模型和癌症患者中，升高的GDF15循环水平与恶病质的发作和进展相关。在某些恶病质动物模型中，不管它们复杂分泌的细胞因子如何，用特异性抗体抑制GDF15的生物活性都可以减轻体重，恢复肌肉和脂肪组织的质量。结论相关观察结果，功能获得和功能丧失实验的结合证明GDF15是癌症恶病质的主要驱动力，并且是治疗和/或预防该综合征的潜在治疗靶标。

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