Meng-Hang Yang1, Bing Li2,3, Ke-Jie Chang4. 1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China. 2. Department of Respiratory and Critical Care Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China. libing1962@smmu.edu.cn. 3. Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China. libing1962@smmu.edu.cn. 4. Department of Thoracic Oncology, Cancer Center of the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China. changkj@mail.sysu.edu.cn.
Abstract
BACKGROUND: Small cell lung cancer (SCLC) is the most malignant type of lung cancer. We previously reported that arsenic trioxide (As2O3) inhibited tumor initiating cells (TICs) of SCLC in vitro. In the present study, we aimed to identify the above effect in vivo and shed light on its underlying mechanism. METHODS AND RESULTS: TICs were enriched by culturing human SCLC cell line as sphere cells in specified serum-free medium. The expression of stem cell markers, CD133 and CD44, and the in vivo tumorigenicity of both TICs and their parental cells were examined. To demonstrate the inhibitory effect of As2O3 on TICs, cell proliferation, clone formation and sphere formation assays were performed. CD133 and Notch pathway-related factors were also measured after As2O3 treatment. Xenograft models were established by injecting TICs into nude mice. Mice were treated with As2O3 for 14 days. Afterwards, the tumor volume and the expression of CD133 and Notch1 were evaluated. TICs obtained by the above-mentioned method showed elevated levels of stem cell markers and increased tumorigenicity compared with their parental cells. As2O3 treatment largely inhibited TICs proliferation, sphere formation and clonogenic capacity. As2O3 also reduced the expression of CD133 and down-regulated Notch pathway in TICs. Furthermore, As2O3 potently inhibited tumor growth, decreased the expression of CD133 and down-regulated Notch1 in tumors originating from TICs. CONCLUSIONS: Our data demonstrate that As2O3 has a remarkable inhibitory effect on TICs of SCLC both in vitro and in vivo, and the mechanism might involve the down-regulation of Notch pathway.
BACKGROUND: Small cell lung cancer (SCLC) is the most malignant type of lung cancer. We previously reported that arsenic trioxide (As2O3) inhibited tumor initiating cells (TICs) of SCLC in vitro. In the present study, we aimed to identify the above effect in vivo and shed light on its underlying mechanism. METHODS AND RESULTS: TICs were enriched by culturing human SCLC cell line as sphere cells in specified serum-free medium. The expression of stem cell markers, CD133 and CD44, and the in vivo tumorigenicity of both TICs and their parental cells were examined. To demonstrate the inhibitory effect of As2O3 on TICs, cell proliferation, clone formation and sphere formation assays were performed. CD133 and Notch pathway-related factors were also measured after As2O3 treatment. Xenograft models were established by injecting TICs into nude mice. Mice were treated with As2O3 for 14 days. Afterwards, the tumor volume and the expression of CD133 and Notch1 were evaluated. TICs obtained by the above-mentioned method showed elevated levels of stem cell markers and increased tumorigenicity compared with their parental cells. As2O3 treatment largely inhibited TICs proliferation, sphere formation and clonogenic capacity. As2O3 also reduced the expression of CD133 and down-regulated Notch pathway in TICs. Furthermore, As2O3 potently inhibited tumor growth, decreased the expression of CD133 and down-regulated Notch1 in tumors originating from TICs. CONCLUSIONS: Our data demonstrate that As2O3 has a remarkable inhibitory effect on TICs of SCLC both in vitro and in vivo, and the mechanism might involve the down-regulation of Notch pathway.
Authors: Virginia Tirino; Vincenzo Desiderio; Francesca Paino; Alfredo De Rosa; Federica Papaccio; Marcella La Noce; Luigi Laino; Francesco De Francesco; Gianpaolo Papaccio Journal: FASEB J Date: 2012-09-28 Impact factor: 5.191
Authors: Julie George; Jing Shan Lim; Se Jin Jang; Yupeng Cun; Luka Ozretić; Gu Kong; Frauke Leenders; Xin Lu; Lynnette Fernández-Cuesta; Graziella Bosco; Christian Müller; Ilona Dahmen; Nadine S Jahchan; Kwon-Sik Park; Dian Yang; Anthony N Karnezis; Dedeepya Vaka; Angela Torres; Maia Segura Wang; Jan O Korbel; Roopika Menon; Sung-Min Chun; Deokhoon Kim; Matt Wilkerson; Neil Hayes; David Engelmann; Brigitte Pützer; Marc Bos; Sebastian Michels; Ignacija Vlasic; Danila Seidel; Berit Pinther; Philipp Schaub; Christian Becker; Janine Altmüller; Jun Yokota; Takashi Kohno; Reika Iwakawa; Koji Tsuta; Masayuki Noguchi; Thomas Muley; Hans Hoffmann; Philipp A Schnabel; Iver Petersen; Yuan Chen; Alex Soltermann; Verena Tischler; Chang-min Choi; Yong-Hee Kim; Pierre P Massion; Yong Zou; Dragana Jovanovic; Milica Kontic; Gavin M Wright; Prudence A Russell; Benjamin Solomon; Ina Koch; Michael Lindner; Lucia A Muscarella; Annamaria la Torre; John K Field; Marko Jakopovic; Jelena Knezevic; Esmeralda Castaños-Vélez; Luca Roz; Ugo Pastorino; Odd-Terje Brustugun; Marius Lund-Iversen; Erik Thunnissen; Jens Köhler; Martin Schuler; Johan Botling; Martin Sandelin; Montserrat Sanchez-Cespedes; Helga B Salvesen; Viktor Achter; Ulrich Lang; Magdalena Bogus; Peter M Schneider; Thomas Zander; Sascha Ansén; Michael Hallek; Jürgen Wolf; Martin Vingron; Yasushi Yatabe; William D Travis; Peter Nürnberg; Christian Reinhardt; Sven Perner; Lukas Heukamp; Reinhard Büttner; Stefan A Haas; Elisabeth Brambilla; Martin Peifer; Julien Sage; Roman K Thomas Journal: Nature Date: 2015-07-13 Impact factor: 49.962
Authors: Francesco Gelsomino; Giuseppe Lamberti; Claudia Parisi; Laura Casolari; Barbara Melotti; Francesca Sperandi; Andrea Ardizzoni Journal: Cancer Treat Rev Date: 2019-08-08 Impact factor: 12.111
Authors: Sana Sarvi; Alison C Mackinnon; Nicolaos Avlonitis; Mark Bradley; Robert C Rintoul; Doris M Rassl; Wei Wang; Stuart J Forbes; Christopher D Gregory; Tariq Sethi Journal: Cancer Res Date: 2014-01-16 Impact factor: 12.701