Development and characterization of a cancer cachexia model employing a rare human duodenal neuroendocrine carcinoma-originating cell line

Abstract

// Kazuyoshi Yanagihara 1, 6 , Takanori Kubo 2 , Yuki Iino 1 , Keichiro Mihara 3 , Chie Morimoto 4 , Toshio Seyama 2 , Takeshi Kuwata 5 , Atsushi Ochiai 1 and Hiroshi Yokozaki 6 1 Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan 2 Department of Life Sciences, Yasuda Women’s University Faculty of Pharmacy, Hiroshima, Japan 3 Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan 4 Department of Living Science Nutrition Course, Matsuyama Shinonome Junior College, Matsuyama, Japan 5 Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan 6 Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan Correspondence to: Kazuyoshi Yanagihara, email: kyanagih@east.ncc.go.jp Keywords: angiogenesis, cancer cachexia, duodenal neuroendocrine carcinoma, IL-8, orthotopic animal model Received: December 18, 2018     Accepted: February 15, 2019     Published: March 29, 2019 ABSTRACT Cancer cachexia interferes with therapy and worsens patients’ quality of life. Therefore, for a better understanding of cachexia, we aimed to establish a reliable cell line to develop a cachexia model. We recently established and characterized the TCC-NECT-2 cell line, derived from a Japanese patient with poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC). Subcutaneous xenograft of TCC-NECT-2 cells in mice resulted in tumor formation, angiogenesis, and 20% incidence of body weight (BW)-loss. Subsequently, we isolated a potent cachexia-inducing subline using stepwise selection and designated as AkuNEC. Orthotopic and s.c. implantation of AkuNEC cells into mice led to diminished BW, anorexia, skeletal muscle atrophy, adipose tissue loss, and decreased locomotor activity at 100% incidence. Additionally, orthotopic implantation of AkuNEC cells resulted in metastasis and angiogenesis. Serum IL-8 overproduction was observed, and levels were positively correlated with BW-loss and reduced adipose tissue and muscle volumes in tumor-bearing mice. However, shRNA knockdown of the IL-8 gene did not suppress tumor growth and cachexia in the AkuNEC model, indicating that IL-8 is not directly involved in cachexia induction. In conclusion, AkuNEC cells may serve as a useful model to study cachexia and D-NEC.