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Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

BACKGROUND: Primary retroperitoneal liposarcomas (RLPSs) are rare heterogeneous tumors for which there are few effective therapies. Certain anti-angiogenic tyrosine kinase inhibitors have demonstrated efficacy against various solid tumors. The aims of this study were to investigate the effect of Apa...

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Autores principales: Cui, Lixuan, Yan, Liang, Guan, Xiaoya, Dong, Bin, Zhao, Min, Lv, Ang, Liu, Daoning, Wang, Zhen, Liu, Faqiang, Wu, Jianhui, Tian, Xiuyun, Hao, Chunyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637299/
https://www.ncbi.nlm.nih.gov/pubmed/34868934
http://dx.doi.org/10.3389/fonc.2021.739139
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author Cui, Lixuan
Yan, Liang
Guan, Xiaoya
Dong, Bin
Zhao, Min
Lv, Ang
Liu, Daoning
Wang, Zhen
Liu, Faqiang
Wu, Jianhui
Tian, Xiuyun
Hao, Chunyi
author_facet Cui, Lixuan
Yan, Liang
Guan, Xiaoya
Dong, Bin
Zhao, Min
Lv, Ang
Liu, Daoning
Wang, Zhen
Liu, Faqiang
Wu, Jianhui
Tian, Xiuyun
Hao, Chunyi
author_sort Cui, Lixuan
collection PubMed
description BACKGROUND: Primary retroperitoneal liposarcomas (RLPSs) are rare heterogeneous tumors for which there are few effective therapies. Certain anti-angiogenic tyrosine kinase inhibitors have demonstrated efficacy against various solid tumors. The aims of this study were to investigate the effect of Apatinib against retroperitoneal liposarcoma cells and its underlying mechanism and to explore the anti-tumor efficacy of a combination of Apatinib and Epirubicin. METHODS: CD34 immunohistochemical staining was used to measure microvessel density (MVD) in 89 retroperitoneal liposarcoma tissues. We used CCK-8 cell proliferation, clone formation, Transwell migration, invasion assays and flow cytometry to evaluate the effects of Apatinib alone and the combination of Apatinib and Epirubicin on liposarcoma cells. High-throughput RNA sequencing and western-blotting was used to identify key differentially expressed genes (DEGs) in SW872 cell line after application of Apatinib. Murine patient-derived tumor xenograft (PDX) was established to assess the efficacy and safety of Apatinib monotherapy and the combination of Apatinib and Epirubicin in RLPS. RESULTS: The microvessel density (MVD) varied widely among retroperitoneal liposarcoma tissues. Compared with the low-MVD group, the high-MVD group had poorer overall survival. Apatinib inhibited the liposarcoma cell proliferation, invasion and migration, increased the proportion of apoptosis, and induced G1 phase arrest. In addition, the combination of Apatinib and Epirubicin enhanced the foregoing inhibitory effects. High-throughput RNA sequencing showed that Apatinib downregulated the expression of TYMS and RRM2. Western blotting verified that Apatinib downregulated the TYMS/STAT3/PD-L1 pathway and inhibited liposarcoma proliferation by suppressing the RRM2/PI3K/AKT/mTOR pathway. In the murine PDX model of retroperitoneal liposarcoma, Apatinib and its combination with Epirubicin significantly inhibited microvessel formation and repressed tumor growth safely and effectively. CONCLUSIONS: Apatinib and its combination with Epirubicin showed strong efficacy against liposarcoma both in vitro and in vivo. Apatinib might inhibit liposarcoma cell proliferation through the RRM2/PI3K/AKT/mTOR signaling pathway and downregulate PD-L1 via the TYMS/STAT3 signaling pathway.
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spelling pubmed-86372992021-12-03 Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma Cui, Lixuan Yan, Liang Guan, Xiaoya Dong, Bin Zhao, Min Lv, Ang Liu, Daoning Wang, Zhen Liu, Faqiang Wu, Jianhui Tian, Xiuyun Hao, Chunyi Front Oncol Oncology BACKGROUND: Primary retroperitoneal liposarcomas (RLPSs) are rare heterogeneous tumors for which there are few effective therapies. Certain anti-angiogenic tyrosine kinase inhibitors have demonstrated efficacy against various solid tumors. The aims of this study were to investigate the effect of Apatinib against retroperitoneal liposarcoma cells and its underlying mechanism and to explore the anti-tumor efficacy of a combination of Apatinib and Epirubicin. METHODS: CD34 immunohistochemical staining was used to measure microvessel density (MVD) in 89 retroperitoneal liposarcoma tissues. We used CCK-8 cell proliferation, clone formation, Transwell migration, invasion assays and flow cytometry to evaluate the effects of Apatinib alone and the combination of Apatinib and Epirubicin on liposarcoma cells. High-throughput RNA sequencing and western-blotting was used to identify key differentially expressed genes (DEGs) in SW872 cell line after application of Apatinib. Murine patient-derived tumor xenograft (PDX) was established to assess the efficacy and safety of Apatinib monotherapy and the combination of Apatinib and Epirubicin in RLPS. RESULTS: The microvessel density (MVD) varied widely among retroperitoneal liposarcoma tissues. Compared with the low-MVD group, the high-MVD group had poorer overall survival. Apatinib inhibited the liposarcoma cell proliferation, invasion and migration, increased the proportion of apoptosis, and induced G1 phase arrest. In addition, the combination of Apatinib and Epirubicin enhanced the foregoing inhibitory effects. High-throughput RNA sequencing showed that Apatinib downregulated the expression of TYMS and RRM2. Western blotting verified that Apatinib downregulated the TYMS/STAT3/PD-L1 pathway and inhibited liposarcoma proliferation by suppressing the RRM2/PI3K/AKT/mTOR pathway. In the murine PDX model of retroperitoneal liposarcoma, Apatinib and its combination with Epirubicin significantly inhibited microvessel formation and repressed tumor growth safely and effectively. CONCLUSIONS: Apatinib and its combination with Epirubicin showed strong efficacy against liposarcoma both in vitro and in vivo. Apatinib might inhibit liposarcoma cell proliferation through the RRM2/PI3K/AKT/mTOR signaling pathway and downregulate PD-L1 via the TYMS/STAT3 signaling pathway. Frontiers Media S.A. 2021-11-18 /pmc/articles/PMC8637299/ /pubmed/34868934 http://dx.doi.org/10.3389/fonc.2021.739139 Text en Copyright © 2021 Cui, Yan, Guan, Dong, Zhao, Lv, Liu, Wang, Liu, Wu, Tian and Hao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Cui, Lixuan
Yan, Liang
Guan, Xiaoya
Dong, Bin
Zhao, Min
Lv, Ang
Liu, Daoning
Wang, Zhen
Liu, Faqiang
Wu, Jianhui
Tian, Xiuyun
Hao, Chunyi
Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title_full Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title_fullStr Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title_full_unstemmed Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title_short Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title_sort anti-tumor effect of apatinib and relevant mechanisms in liposarcoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637299/
https://www.ncbi.nlm.nih.gov/pubmed/34868934
http://dx.doi.org/10.3389/fonc.2021.739139
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