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阿帕替尼通过抑制音猬因子信号通路抑制胃癌干细胞特性。

Apatinib Suppresses Gastric Cancer Stem Cells Properties by Inhibiting the Sonic Hedgehog Pathway.

作者信息

Cao Wanshuang, Li Yuan, Sun Hongliang, Yang Chenying, Zhu Jianyun, Xie Chunfeng, Li Xiaoting, Wu Jieshu, Geng Shanshan, Wang Lu, Sun Liangfei, Geng Guozhu, Han Hongyu, Zhong Caiyun

机构信息

Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Department of Clinical Nutrition, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

出版信息

Front Cell Dev Biol. 2021 Jul 19;9:679806. doi: 10.3389/fcell.2021.679806. eCollection 2021.

DOI:10.3389/fcell.2021.679806
PMID:34350176
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8326764/
Abstract

The presence of gastric cancer stem cells (GCSCs) marks the onset of gastric carcinoma. The sonic hedgehog (SHH) pathway plays a vital role in the maintenance of GCSC characteristics. Apatinib has been approved in China for advanced gastric cancer (GC) treatment. However, whether apatinib can target GCSCs and affect the SHH pathway remains unclear. The present study aimed to investigate the underlying mechanism of apatinib's antitumor effects on GC. The expression levels of GCSC markers and number of CD133 cells were significantly elevated in the sphere-forming cells. Apatinib effectively suppressed GCSC traits by inhibiting tumorsphere formation and cell proliferation, suppressing GCSC markers expression and CD133 cell number, and inducing apoptosis. Apatinib downregulated the activation of the SHH pathway; while upregulation of the SHH pathway attenuated the inhibitory effects of apatinib on GCSCs. Moreover, apatinib treatment significantly delayed tumor growth and inhibited GCSC characteristics in the xenograft model. Our data suggested that apatinib exhibited inhibitory effects on GCSCs by suppressing SHH pathway both and , thus providing new insights into the therapeutic application of apatinib in GCSC suppression and advanced gastric cancer treatment.

摘要

胃癌干细胞（GCSCs）的存在标志着胃癌的发生。音猬因子（SHH）信号通路在维持GCSCs特性方面起着至关重要的作用。阿帕替尼在中国已被批准用于晚期胃癌（GC）的治疗。然而，阿帕替尼是否能靶向GCSCs并影响SHH信号通路仍不清楚。本研究旨在探讨阿帕替尼对GC抗肿瘤作用的潜在机制。在成球细胞中，GCSC标志物的表达水平和CD133阳性细胞数量显著升高。阿帕替尼通过抑制肿瘤球形成和细胞增殖、抑制GCSC标志物表达和CD133阳性细胞数量以及诱导凋亡，有效抑制了GCSCs的特性。阿帕替尼下调了SHH信号通路的激活；而SHH信号通路的上调减弱了阿帕替尼对GCSCs的抑制作用。此外，在异种移植模型中，阿帕替尼治疗显著延迟了肿瘤生长并抑制了GCSCs的特性。我们的数据表明，阿帕替尼通过抑制SHH信号通路对GCSCs具有抑制作用，从而为阿帕替尼在抑制GCSCs和治疗晚期胃癌方面的治疗应用提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/3465f0f723ca/fcell-09-679806-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/206c7092e65f/fcell-09-679806-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/a9c71517cc37/fcell-09-679806-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/080ef043c7ac/fcell-09-679806-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/bfba61f1a101/fcell-09-679806-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/bee3df66ed17/fcell-09-679806-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/f3d5ddc43d04/fcell-09-679806-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/3465f0f723ca/fcell-09-679806-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/206c7092e65f/fcell-09-679806-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/a9c71517cc37/fcell-09-679806-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/080ef043c7ac/fcell-09-679806-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/bfba61f1a101/fcell-09-679806-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/bee3df66ed17/fcell-09-679806-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/f3d5ddc43d04/fcell-09-679806-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa4/8326764/3465f0f723ca/fcell-09-679806-g007.jpg

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