Yoo Wonbeak, Choi Hyunji, Son Young Hoon, Lee Jaemin, Jo Seongyea, Jung Dana, Kim Yeon Jeong, Koh Sang Seok, Yang Yong Ryoul, Kwon Eun-Soo, Lee Kwang-Pyo, Noh Kyung Hee, Kim Kyung Won, Ko Yousun, Jun Eunsung, Kim Song Cheol, Kim Seokho
Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 34134, Republic of Korea.
Exp Mol Med. 2021 Mar;53(3):432-445. doi: 10.1038/s12276-021-00582-2. Epub 2021 Mar 17.
Cancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.
癌症恶病质是一种高度衰弱的病症，其特征为体重减轻和肌肉萎缩，这对胰腺癌的发病率和死亡率有显著影响。导致胰腺癌恶病质的因素在很大程度上尚不清楚。我们之前表明，胰腺癌细胞分泌的胰腺腺癌上调因子（PAUF）与肿瘤生长和转移有关。在此，我们分析了胰腺癌来源的PAUF与小鼠癌症恶病质之间的关系及其临床意义。携带Panc-1/PAUF肿瘤的小鼠体重减轻和肌肉重量减轻显著高于携带Panc-1/Mock肿瘤的小鼠。将重组PAUF直接注射到肌肉中可重现肿瘤诱导的萎缩，而PAUF中和抗体可消除携带Panc-1/PAUF肿瘤小鼠的肿瘤诱导的肌肉萎缩。用重组PAUF处理的C2C12肌管表现出Akt-Foxo3a信号快速失活，导致Atrogin1/MAFbx上调、肌球蛋白重链丢失和肌肉萎缩。PAUF高表达的胰腺癌患者的中性粒细胞与淋巴细胞比率和体重减轻显著高于PAUF低表达的患者。对不同胰腺癌数据集的分析表明，胰腺癌组中PAUF表达显著高于非肿瘤组。对癌症基因组图谱数据的分析发现，PAUF高表达或高DNA拷贝数与总体生存率低之间存在关联。我们的数据确定肿瘤分泌的循环PAUF是恶病质的关键因素，可导致小鼠肌肉萎缩。中和PAUF可能是治疗胰腺癌诱导的恶病质的一种有用治疗策略。
