2. Academic Validation
  3. Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor

Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor

  • Exp Mol Med. 2021 Mar;53(3):432-445. doi: 10.1038/s12276-021-00582-2.
Wonbeak Yoo # 1,  Hyunji Choi # 2,  Young Hoon Son # 3,  Jaemin Lee 4,  Seongyea Jo 5,  Dana Jung 6,  Yeon Jeong Kim 7,  Sang Seok Koh 7,  Yong Ryoul Yang 3,  Eun-Soo Kwon 3,  Kwang-Pyo Lee 3,  Kyung Hee Noh 8,  Kyung Won Kim 9,  Yousun Ko 9,  Eunsung Jun 10,  Song Cheol Kim 11 12,  Seokho Kim 13 14
Affiliations

Affiliations

  • 1 Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 2 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 3 Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 4 Industrial Bio-Materials Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 5 Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea.
  • 6 Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea.
  • 7 Department of Biological Sciences, Dong-A University, Busan, 49315, Republic of Korea.
  • 8 Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 9 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
  • 10 Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, 05505, Republic of Korea. eunsungjun@amc.seoul.kr.
  • 11 Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, 05505, Republic of Korea. drksc@amc.seoul.kr.
  • 12 Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. drksc@amc.seoul.kr.
  • 13 Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea. cvaccine@dau.ac.kr.
  • 14 Department of Medicinal Biotechnology, College of Health science, Dong-A University, Busan, 49315, Republic of Korea. cvaccine@dau.ac.kr.
  • # Contributed equally.
PMID: 33731895 DOI: 10.1038/s12276-021-00582-2
Abstract

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.

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