Suppression of Skeletal Muscle Turnover in Cancer Cachexia: Evidence from the Transcriptome in Sequential Human Muscle Biopsies
Suppression of Skeletal Muscle Turnover in Cancer Cachexia: Evidence from the Transcriptome in Sequential Human Muscle Biopsies
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DOI：
10.1158/1078-0432.ccr-11-2133
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发表时间：
2012-05-15
影响因子：
11.5
通讯作者：
Fearon, Kenneth C. H.
中科院分区：
文献类型：
--
作者：
Gallagher, Iain J.;Stephens, Nathan A.;Fearon, Kenneth C. H.
目的：癌症患者肌肉萎缩的机制尚不清楚，因此对新的生物标志物和治疗策略的临床需求仍未得到满足。实验设计：使用微阵列检测来自健康对照组(n=6)的单个活检组织和来自上消化道肿瘤患者(UGIC；n=12)的成对活检组织[手术前基线(体重减轻7%)和术后8个月随访(无病/体重稳定前2个月)]中的转录组。结果：手术前，1,868个基因被调控(假发现率为6%)。本体论分析表明，在基线样本中，调控基因同时属于合成代谢和分解代谢的生物过程，并存在压倒性的下调。没有来自临床前癌症恶病质模型的文献来源的基因在基线肌肉中有更高的表达。与健康对照肌肉(n=6)的比较显示，尽管基线时的转录组存在差异(941个调控基因)，但患者随访时的肌肉与对照肌肉相似(2个调控基因)。体力活动(每天的步数)在基线和随访期之间没有差异(P=0.9)，表明基因表达的差异反映了癌症的去除，而不是体力活动水平的改变。使用运动训练信号的比较基因表达分析支持这一解释。结论：在患有UGIC的减肥患者中，代谢和蛋白质周转相关的途径受到抑制，而癌症的移除似乎促进了健康状态的恢复，与体力活动水平的变化无关。临床癌症资源；18(10)；2817-27。(C)2012年AACR。
Purpose: The mechanisms underlying muscle wasting in patients with cancer remain poorly understood, and consequently there remains an unmet clinical need for new biomarkers and treatment strategies.Experimental Design: Microarrays were used to examine the transcriptome in single biopsies from healthy controls (n = 6) and in paired biopsies [pre-resection baseline (weight-loss 7%) and 8 month post-resection follow-up (disease-free/weight-stable for previous 2 months)] from quadriceps muscle of patients with upper gastrointestinal cancer (UGIC; n = 12).Results: Before surgery, 1,868 genes were regulated compared with follow-up (false discovery rate, 6%). Ontology analysis showed that regulated genes belonged to both anabolic and catabolic biologic processes with overwhelming downregulation in baseline samples. No literature-derived genes from preclinical cancer cachexia models showed higher expression in baseline muscle. Comparison with healthy control muscle (n = 6) revealed that despite differences in the transcriptome at baseline (941 genes regulated), the muscle of patients at follow-up was similar to control muscle (2 genes regulated). Physical activity (step count per day) did not differ between the baseline and follow-up periods (P = 0.9), indicating that gene expression differences reflected the removal of the cancer rather than altered physical activity levels. Comparative gene expression analysis using exercise training signatures supported this interpretation.Conclusions: Metabolic and protein turnover-related pathways are suppressed in weight-losing patients with UGIC whereas removal of the cancer appears to facilitate a return to a healthy state, independent of changes in the level of physical activity. Clin Cancer Res; 18(10); 2817-27. (C)2012 AACR.