Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

BackgroundPrimary 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 Apati...

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Autores principales:	Lixuan Cui, Liang Yan, Xiaoya Guan, Bin Dong, Min Zhao, Ang Lv, Daoning Liu, Zhen Wang, Faqiang Liu, Jianhui Wu, Xiuyun Tian, Chunyi Hao
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	primary retroperitoneal liposarcoma angiogenesis apatinib epirubicin microvessel density Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d2a6f6e5bd56444da45cbfd8cb6791e7
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spelling	oai:doaj.org-article:d2a6f6e5bd56444da45cbfd8cb6791e72021-11-18T08:28:30ZAnti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma2234-943X10.3389/fonc.2021.739139https://doaj.org/article/d2a6f6e5bd56444da45cbfd8cb6791e72021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.739139/fullhttps://doaj.org/toc/2234-943XBackgroundPrimary 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.MethodsCD34 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.ResultsThe 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.ConclusionsApatinib 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.Lixuan CuiLiang YanXiaoya GuanBin DongMin ZhaoAng LvDaoning LiuZhen WangFaqiang LiuJianhui WuXiuyun TianChunyi HaoFrontiers Media S.A.articleprimary retroperitoneal liposarcomaangiogenesisapatinibepirubicinmicrovessel densityNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	primary retroperitoneal liposarcoma angiogenesis apatinib epirubicin microvessel density Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	primary retroperitoneal liposarcoma angiogenesis apatinib epirubicin microvessel density Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Lixuan Cui Liang Yan Xiaoya Guan Bin Dong Min Zhao Ang Lv Daoning Liu Zhen Wang Faqiang Liu Jianhui Wu Xiuyun Tian Chunyi Hao Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
description	BackgroundPrimary 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.MethodsCD34 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.ResultsThe 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.ConclusionsApatinib 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.
format	article
author	Lixuan Cui Liang Yan Xiaoya Guan Bin Dong Min Zhao Ang Lv Daoning Liu Zhen Wang Faqiang Liu Jianhui Wu Xiuyun Tian Chunyi Hao
author_facet	Lixuan Cui Liang Yan Xiaoya Guan Bin Dong Min Zhao Ang Lv Daoning Liu Zhen Wang Faqiang Liu Jianhui Wu Xiuyun Tian Chunyi Hao
author_sort	Lixuan Cui
title	Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
title_short	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_sort	anti-tumor effect of apatinib and relevant mechanisms in liposarcoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d2a6f6e5bd56444da45cbfd8cb6791e7
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Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

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