Establishment of a novel experimental model for muscle-invasive bladder cancer by using dog bladder cancer organoid culture.

Bladder cancer (BC) is the most common neoplasm affecting the urinary tract in human and dogs. Since dog BC resembles muscle-invasive BC in human with regards to histopathological characteristics and gene expression profiles, it is expected to become a precious research model of human muscle-invasive BC. Cancer patient-derived organoid culture can recapitulate organ structures and maintain gene expression profiles of original tumor tissues. In the previous study, we generated dog prostate cancer organoids using the urine samples. However, dog BC organoids have never been developed. We therefore tried to generate dog BC organoids using the urine samples and to check their histopathological characteristics, drug sensitivity, and gene expression profiles. Organoids from each BC dog were successfully generated, which expressed urothelial cell markers (CK7, CK20, and UPK3A) and exhibited tumorigenesis in vivo. In the cell viability assay, the responsiveness to combination treatment with anti-cancer drugs (cisplatin, vinblastine, gemcitabine or piroxicam) was markedly different in each BC organoid. In the RNA sequencing analysis, expression of basal cell markers (CK5 and DSG3) and several novel genes (MMP28, CTSE, CNN3, TFPI2, COL17A1, and AGPAT4) were upregulated in the BC organoids compared with normal bladder tissues or two-dimensional (2D) BC cell lines. These findings revealed that our established dog BC organoids might become a useful tool not only for determining the proper chemotherapy in BC diseased dogs but also identifying novel biomarkers in human muscle-invasive BC. This article is protected by copyright. All rights reserved.

Cancer science. 2019 Jun 29 [Epub ahead of print]

Mohamed Elbadawy, Tatsuya Usui, Takashi Mori, Ryouichi Tsunedomi, Shoichi Hazama, Rina Nabeta, Tsuyoshi Uchide, Ryuji Fukushima, Toshinori Yoshida, Makoto Shibutani, Takaharu Tanaka, Sosuke Masuda, Rena Okada, Ryo Ichikawa, Tsutomu Omatsu, Tetsuya Mizutani, Yukie Katayama, Shunsuke Noguchi, Satomi Iwai, Takayuki Nakagawa, Yuta Shinohara, Masahiro Kaneda, Hideyuki Yamawaki, Kazuaki Sasaki

Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan., Laboratory of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, 1-1, Yanagido, Gifu, Gifu, 501-1193, Japan., Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan., Department of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan., Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan., Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan., Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan., Laboratory of Veterinary Radiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuouraikita, Sano, Osaka, 598-8531, Japan., Laboratory of Small Animal Surgery 2, School of Veterinary Medicine, Kitasato University, 35-1, Higashi 23 ban-cho, Towada, Aomori, 034-8628, Japan., Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan., Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan., Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, 35-1, Higashi 23 ban-cho, Towada, Aomori, 034-8628, Japan.

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