Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells

类有机物 食管鳞状细胞癌 基底细胞 医学 肿瘤科 内科学 病理 生物 细胞生物学
作者
Takashi Kijima,Hiroshi Nakagawa,Masataka Shimonosono,Prasanna M. Chandramouleeswaran,Takeo Hara,Varun Sahu,Yuta Kasagi,Osamu Kikuchi,Koji Tanaka,Véronique Giroux,Amanda B. Muir,Kelly A. Whelan,Shinya Ohashi,Seiji Naganuma,Andres J. Klein‐Szanto,Yoshiaki Shinden,Ken Sasaki,Itaru Omoto,Yoshiaki Kita,Manabu Muto,Adam J. Bass,J. Alan Diehl,Gregory G. Ginsberg,Yuichiro� Doki,Masaki Mori,Yasuto Uchikado,Takaaki Arigami,Narayan G. Avadhani,Devraj Basu,Anil K. Rustgi,Shoji Natsugoe
出处
期刊:Cellular and molecular gastroenterology and hepatology [Elsevier BV]
卷期号:7 (1): 73-91 被引量:124
标识
DOI:10.1016/j.jcmgh.2018.09.003
摘要

Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas.We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo.Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment.The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine.
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