Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia
Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia
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DOI：
10.1002/jcsm.12561
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发表时间：
2020-08-01
影响因子：
8.9
通讯作者：
Riuzzi, Francesca
中科院分区：
文献类型：
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作者：
Chiappalupi, Sara;Sorci, Guglielmo;Riuzzi, Francesca
背景恶病质是一种多因素综合征，影响超过50%的晚期癌症患者，约占癌症相关死亡的20%，仍然是一个知之甚少的过程，没有标准的治疗方法。由全身性炎症引起的骨骼肌萎缩是恶病质的主要临床特征，导致体重减轻，降低患者的生活质量，并降低患者对抗癌治疗的反应。晚期糖基化终产物受体（receptor for advanced glycation end-products，AGEs）是免疫球蛋白超家族的多配体受体，也是肌肉再生、炎症和癌症的介质。方法采用BALB/c、C57 BL/6或Ager（-/-）小鼠结肠腺癌（C26-ADK）或刘易斯肺癌（LLC）细胞接种小鼠模型，（RAGE-无效）小鼠，我们研究了在癌症恶病质的主要特征中，使用来自C2 C12成肌细胞或分离自C57 BL/6野生型和Ager（-/-）的原代成肌细胞的肌管进行体外实验。用TNF配体、S100 B（S100钙结合蛋白B）、TNF（肿瘤坏死因子）α +/- IFN（干扰素）γ和肿瘤细胞或肿瘤块条件培养基处理的小鼠，以分析肌肉萎缩的标志。最后，在无肿瘤的环境中，用TNF α/IFN γ或S100 B注射野生型和Ager（-/-）小鼠的肌肉。结果我们证明，在促炎细胞因子和/或肿瘤源性恶病质诱导因子的存在下，p53是激活导致肌肉蛋白降解的信号通路的决定因素。我们鉴定了S100 B配体作为一种新的能够通过p38 MAPK（p38丝裂原活化蛋白激酶）/肌细胞生成素轴和STAT 3（信号转导和转录激活因子3）依赖性MyoD（成肌细胞决定蛋白1）降解诱导肌肉萎缩的因子。最后，我们发现，在癌症条件下，肿瘤来源的S100 B和HMGB 1（高迁移率族蛋白1）的血清水平增加，导致慢性激活/过度表达的HMGB 1，这诱导癌症恶病质的标志（即肌肉萎缩，全身性炎症和肿瘤来源的前恶病质因子的释放）。在小鼠中，如果没有这种蛋白质，则会导致恶病质诱导因子的血清水平降低，肌肉质量和力量的损失延迟，肿瘤进展减少，存活率增加。结论肿瘤恶病质是肿瘤恶病质发生的分子决定因素，靶向治疗肿瘤恶病质可能是预防或对抗恶病质综合征的一种治疗策略。
Background Cachexia, a multifactorial syndrome affecting more than 50% of patients with advanced cancer and responsible for ~20% of cancer-associated deaths, is still a poorly understood process without a standard cure available. Skeletal muscle atrophy caused by systemic inflammation is a major clinical feature of cachexia, leading to weight loss, dampening patients' quality of life, and reducing patients' response to anticancer therapy. RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily and a mediator of muscle regeneration, inflammation, and cancer. Methods By using murine models consisting in the injection of colon 26 murine adenocarcinoma (C26-ADK) or Lewis lung carcinoma (LLC) cells in BALB/c and C57BL/6 orAger(-/-)(RAGE-null) mice, respectively, we investigated the involvement of RAGE signalling in the main features of cancer cachexia, including the inflammatory state.In vitroexperiments were performed using myotubes derived from C2C12 myoblasts or primary myoblasts isolated from C57BL/6 wild type andAger(-/-)mice treated with the RAGE ligand, S100B (S100 calcium-binding protein B), TNF (tumor necrosis factor)alpha +/- IFN (interferon) gamma, and tumour cell- or masses-conditioned media to analyse hallmarks of muscle atrophy. Finally, muscles of wild type andAger(-/-)mice were injected with TNF alpha/IFN gamma or S100B in a tumour-free environment. Results We demonstrate that RAGE is determinant to activate signalling pathways leading to muscle protein degradation in the presence of proinflammatory cytokines and/or tumour-derived cachexia-inducing factors. We identify the RAGE ligand, S100B, as a novel factor able to induce muscle atrophyper sevia a p38 MAPK (p38 mitogen-activated protein kinase)/myogenin axis and STAT3 (signal transducer and activator of transcription 3)-dependent MyoD (myoblast determination protein 1) degradation. Lastly, we found that in cancer conditions, an increase in serum levels of tumour-derived S100B and HMGB1 (high mobility group box 1) occurs leading to chronic activation/overexpression of RAGE, which induces hallmarks of cancer cachexia (i.e. muscle wasting, systemic inflammation, and release of tumour-derived pro-cachectic factors). Absence of RAGE in mice translates into reduced serum levels of cachexia-inducing factors, delayed loss of muscle mass and strength, reduced tumour progression, and increased survival. Conclusions RAGE is a molecular determinant in inducing the hallmarks of cancer cachexia, and molecular targeting of RAGE might represent a therapeutic strategy to prevent or counteract the cachectic syndrome.