Pulmonology Department-Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer, Health and Experimental Sciences Department (CEXS), MIM-Hospital del Mar, Parc de Salut Mar, Universitat Pompeu Fabra, Barcelona, Spain.
Centro de Investigación en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
J Cell Physiol. 2019 Aug;234(10):18041-18052. doi: 10.1002/jcp.28437. Epub 2019 Mar 9.
Identification of to what extent tumor burden influences muscle mass independently of specific treatments for cancer-cachexia remains to be elucidated. We hypothesized that reduced tumor burden by selective treatment of tumor with immunomodulators may exert beneficial effects on muscle wasting and function in mice. Body and muscle weight, grip strength, physical activity, muscle morphometry, apoptotic nuclei, troponin-I systemic levels, interleukin-6, proteolytic markers, and tyrosine release, and apoptosis markers were determined in diaphragm and gastrocnemius muscles of lung cancer (LP07 adenocarcinoma cells) mice (BALB/c) treated with monoclonal antibodies (mAbs), against immune check-points and pathways (CD-137, cytotoxic T-lymphocyte associated protein-4, programed cell death-1, and CD-19; N = 10/group). Nontreated lung cancer cachectic mice were the controls. T and B cell numbers and macrophages were counted in tumors of both mouse groups. Compared to nontreated cachectic mice, in the mAbs-treated animals, T cells increased, no differences in B cells or macrophages, the variables final body weight, body weight and grip strength gains significantly improved. In diaphragm and gastrocnemius of mAbs-treated cachectic mice, number of apoptotic nuclei, tyrosine release, proteolysis, and apoptosis markers significantly decreased compared to nontreated cachectic mice. Systemic levels of troponin-I significantly decreased in treated cachectic mice compared to nontreated animals. We conclude that reduced tumor burden as a result of selective treatment of the lung cancer cells with immunomodulators elicits per se beneficial effects on muscle mass loss through attenuation of several biological mechanisms that lead to increased protein breakdown and apoptosis, which translated into significant improvements in limb muscle strength but not in physical activity parameters.
肿瘤负担在多大程度上独立于癌症恶病质的特定治疗影响肌肉质量仍有待阐明。我们假设，通过免疫调节剂选择性治疗肿瘤以减少肿瘤负担，可能会对小鼠的肌肉消耗和功能产生有益影响。在肺癌（LP07 腺癌细胞）小鼠（BALB/c）中，用单克隆抗体（针对免疫检查点和途径的 CD-137、细胞毒性 T 淋巴细胞相关蛋白 4、程序性细胞死亡 1 和 CD-19）治疗后，测定膈肌和腓肠肌的体重和肌肉重量、握力、体力活动、肌肉形态计量学、凋亡核、肌钙蛋白 I 全身水平、白细胞介素 6、蛋白水解标志物和酪氨酸释放以及凋亡标志物（N=10/组）。未治疗的肺癌恶病质小鼠为对照组。计数两组小鼠肿瘤中的 T 和 B 细胞数量和巨噬细胞。与未治疗的恶病质小鼠相比，在 mAb 治疗的动物中，T 细胞增加，B 细胞或巨噬细胞没有差异，最终体重、体重和握力增加等变量显著改善。与未治疗的恶病质小鼠相比，mAb 治疗的恶病质小鼠的膈肌和腓肠肌中的凋亡核、酪氨酸释放、蛋白水解和凋亡标志物数量显著减少。与未治疗的动物相比，mAb 治疗的恶病质小鼠的肌钙蛋白 I 全身水平显著降低。我们得出结论，通过免疫调节剂选择性治疗肺癌细胞减少肿瘤负担本身就会通过减弱导致蛋白质分解和凋亡增加的几种生物学机制，对肌肉质量损失产生有益影响，这转化为四肢肌肉力量的显著改善，但对体力活动参数没有影响。
