摘要:癌症恶病质是通过抑制骨骼肌血管中pgc1 - α的表达而介导的

Young-Mee Kim, Georgina Mancinelli, P. Grippo, J. Rehman
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引用次数: 0

摘要

背景:癌症患者经历恶病质,其特征是广泛的骨骼肌萎缩,使生活质量恶化,死亡率增加。然而,目前还没有被批准的治疗方法可以有效地对抗癌症恶病质。先前的研究主要集中在肌肉组织内部的变化,但对肌肉血管在癌症恶病质中的作用知之甚少。血管内皮细胞(ECs)在维持组织灌注、营养供应和防止免疫细胞不适当地迁移到组织中至关重要。因此,我们假设骨骼肌内皮功能障碍导致癌症中恶病质的发展。转录共激活因子PGC1α(过氧化物酶体增殖激活因子受体-γ共激活因子1-α)调节内皮健康。方法和结果:为了评估骨骼肌EC-PGC1α是否在恶性肿瘤环境下被调节,我们在黑色素瘤植入后1、2和3周从对照和黑色素瘤小鼠中分离肌肉ec。与对照组小鼠相比,黑色素瘤小鼠早期(1周)mec中PGC1α的表达显著降低。因此,我们建立了ec特异性诱导的PGC1α缺失小鼠模型(ECΔPGC1α)来研究EC-PGC1α在体内癌症恶病质中的机制作用。有趣的是,与使用创新的组织清除和高分辨率3d组织成像系统的ECWT小鼠相比,ECΔPGC1α小鼠腓肠肌(GC)的血管密度和肌肉面积显着减少。携带肿瘤的ECWT小鼠通过增强恶病质标记基因MuRF1和Atrogin1,与未携带肿瘤的小鼠相比,减少了GC质量和重量。荷瘤ECΔPGC1α小鼠的肌肉质量、体重和握力比荷瘤ECWT小鼠进一步降低。我们评估了EC-PGC1α在体内毛细血管功能调节中的作用,并观察到ECΔPGC1α小鼠的血管泄漏明显大于ECWT小鼠。结论:黑色素瘤的存在可抑制骨骼肌内皮中PGC1α的表达。反过来,内皮细胞PGC1α对于维持骨骼肌血管屏障的完整性至关重要。我们的研究表明,恢复肌肉内皮功能障碍可能是预防或逆转癌症恶病质的一种新的治疗方法。引文格式:Young-Mee Kim, Georgina Mancinelli, Paul Grippo, Jalees Rehman。癌症恶病质是通过抑制骨骼肌血管中pgc1 - α的表达而介导的[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2595。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract 2595: Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature
Background: Cancer patients experience cachexia which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. However, there are no approved treatments that can effectively counteract cancer cachexia. Prior research has focused on the changes within the muscle tissue but little is known about the role of the muscle vasculature in mediating cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply and preventing inappropriate transmigration of immune cells into the tissue. We therefore hypothesized that endothelial dysfunction in the skeletal muscle results in the development of cachexia in cancer. The transcriptional co-activator PGC1α (peroxisome proliferation activator receptor-γ coactivator1-α) regulates endothelial health. Methods and Results: To evaluate whether skeletal muscle EC-PGC1α is modulated in the setting of malignancy, we isolated muscle ECs from control and melanoma bearing mice at 1, 2, and 3 weeks after melanoma implantation. PGC1α expression was significantly decreased in mECs of melanoma bearing mice from early stage (1 week) compared with control mice. Thus, we generated an EC-specific inducible PGC1α deletion mouse model (ECΔPGC1α) to investigate the mechanistic role of EC-PGC1α in cancer cachexia in vivo. Interestingly, vascular density and muscle area were significantly decreased in the gastrocnemius (GC) of ECΔPGC1α mice compared with ECWT mice using an innovative tissue clearing and high-resolution 3D-tissue imaging system. Tumor bearing ECWT mice had decreased GC mass and weight compared with no tumor mice by enhancing cachexia marker genes, MuRF1 and Atrogin1. The tumor bearing ECΔPGC1α mice had further decreased muscle mass and weight, and grip strength than tumor bearing ECWT mice. We assessed the role of EC-PGC1α in the regulation of capillary function in vivo, and observed that ECΔPGC1α mice demonstrated significantly greater vascular leak than ECWT mice. Conclusion: These data suggest that the presence of melanoma suppresses PGC1α expression in the skeletal muscle endothelium. Endothelial PGC1α, in turn, is essential for maintaining the integrity of the skeletal muscle vascular barrier. Our study suggests that restoring muscle endothelial dysfunction could be a novel therapeutic approach to prevent or reverse cancer cachexia. Citation Format: Young-Mee Kim, Georgina Mancinelli, Paul Grippo, Jalees Rehman. Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2595.
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