Abstract:
Muscle atrophy and weakness are prevalent features of cancer. Although extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naive cancer. Here, the authors used orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, to define the impacts of malignancy on cardiac structure, function, and metabolism. Tumor-bearing mice develop cardiac atrophy and intrinsic systolic and diastolic dysfunction, with arterial hypotension and exercise intolerance. In hearts of ovarian tumor-bearing mice, fatty acid-supported mitochondrial respiration decreased, and carbohydrate-supported respiration increased-showcasing a substrate shift in cardiac metabolism that is characteristic of heart failure. Epithelial ovarian cancer decreased cytoskeletal and cardioprotective gene expression, which was paralleled by down-regulation of transcription factors that regulate cardiomyocyte size and function. Patient-derived pancreatic xenograft tumor-bearing mice show altered myosin heavy chain isoform expression-also a molecular phenotype of heart failure. Markers of autophagy and ubiquitin-proteasome system were upregulated by cancer, providing evidence of catabolic signaling that promotes cardiac wasting. Together, the authors cross-validate with two cancer types, evidence of the structural, functional, and metabolic cancer-induced cardiomyopathy, thus providing translational evidence that could impact future medical management strategies for improved cancer recovery in patients.
摘要:
肌肉萎缩和虚弱是癌症的普遍特征。虽然广泛的研究已经描述了癌症恶病质中骨骼肌萎缩的特征,有限的研究已经调查了心脏结构和功能如何受到初治癌症的影响。这里我们用的是原位的,上皮性卵巢癌(EOC)和胰腺导管腺癌(PDAC)的同基因模型,和患者来源的胰腺异种移植模型(PDX),为了定义恶性肿瘤对心脏结构的影响,函数,和新陈代谢。荷瘤小鼠出现心脏萎缩和内在的收缩和舒张功能障碍,动脉低血压和运动不耐受。在卵巢荷瘤小鼠的心脏中,脂肪酸支持的线粒体呼吸减少,和碳水化合物支持的呼吸增加-显示心脏代谢的底物变化,这是心力衰竭的特征。EOC降低了细胞骨架和心脏保护基因的表达,与调节心肌细胞大小和功能的转录因子下调平行。PDX荷瘤小鼠显示肌球蛋白重链同工型表达改变-也是心力衰竭的分子表型。自噬和泛素-蛋白酶体系统的标志物被癌症上调,提供促进心脏消耗的分解代谢信号的证据。一起,我们交叉验证了两种癌症类型,结构的证据,功能,代谢性癌症诱发的心肌病,从而提供可能影响未来改善患者癌症恢复的医疗管理策略的转化证据.