Cui Lixuan, Yan Liang, Guan Xiaoya, Dong Bin, Zhao Min, Lv Ang, Liu Daoning, Wang Zhen, Liu Faqiang, Wu Jianhui, Tian Xiuyun, Hao Chunyi
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital and Institute, Beijing, China.
Front Oncol. 2021 Nov 18;11:739139. doi: 10.3389/fonc.2021.739139. eCollection 2021.
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.
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.
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.
Apatinib and its combination with Epirubicin showed strong efficacy against liposarcoma both and . Apatinib might inhibit liposarcoma cell proliferation through the RRM2/PI3K/AKT/mTOR signaling pathway and downregulate PD-L1 the TYMS/STAT3 signaling pathway.
原发性腹膜后脂肪肉瘤（RLPS）是罕见的异质性肿瘤，有效治疗方法很少。某些抗血管生成酪氨酸激酶抑制剂已显示出对各种实体瘤的疗效。本研究的目的是探讨阿帕替尼对腹膜后脂肪肉瘤细胞的作用及其潜在机制，并探索阿帕替尼与表柔比星联合使用的抗肿瘤疗效。
采用CD34免疫组化染色检测89例腹膜后脂肪肉瘤组织中的微血管密度（MVD）。我们使用CCK-8细胞增殖、克隆形成、Transwell迁移、侵袭试验和流式细胞术来评估阿帕替尼单独使用以及阿帕替尼与表柔比星联合使用对脂肪肉瘤细胞的影响。应用阿帕替尼后，采用高通量RNA测序和蛋白质免疫印迹法鉴定SW872细胞系中的关键差异表达基因（DEG）。建立小鼠患者来源的肿瘤异种移植（PDX）模型，以评估阿帕替尼单药治疗以及阿帕替尼与表柔比星联合使用对RLPS的疗效和安全性。
腹膜后脂肪肉瘤组织中的微血管密度（MVD）差异很大。与低MVD组相比，高MVD组的总生存期较差。阿帕替尼抑制脂肪肉瘤细胞增殖、侵袭和迁移，增加凋亡比例，并诱导G1期阻滞。此外，阿帕替尼与表柔比星联合使用增强了上述抑制作用。高通量RNA测序显示，阿帕替尼下调TYMS和RRM2的表达。蛋白质免疫印迹法证实，阿帕替尼下调TYMS/STAT3/PD-L1通路，并通过抑制RRM2/PI3K/AKT/mTOR通路抑制脂肪肉瘤增殖。在腹膜后脂肪肉瘤的小鼠PDX模型中，阿帕替尼及其与表柔比星的联合使用均能显著抑制微血管形成，并安全有效地抑制肿瘤生长。
阿帕替尼及其与表柔比星联合使用对脂肪肉瘤均显示出强大疗效。阿帕替尼可能通过RRM2/PI3K/AKT/mTOR信号通路抑制脂肪肉瘤细胞增殖，并通过TYMS/STAT3信号通路下调PD-L1。
