Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3

Zheng, Bingxin; Ren, Tingting; Huang, Yi; Guo, Wei

doi:10.1016/j.bbrc.2017.12.032

Cited by 89Sarcoma Diagnosis and TreatmentAngiogenesis and VEGF in CancerCancer Immunotherapy and Biomarkers

Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3

Zheng, Bingxin, Ren, Tingting, Huang, Yi, Guo, Wei·2018·Biochemical and Biophysical Research Communications

DOI 10.1016/j.bbrc.2017.12.032

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Abstract

The cure rate of osteosarcoma has not improved in the past 30 years. The new treatments and drugs is urgently needed, especially for metastatic osteosarcoma. Anti-angiogenesis therapy and immunotherapy has got promising anti-tumor effects in various tumors. It is hypothesised that combining checkpoint inhibitor immunotherapies with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. However, its underlying mechanism remain largely uninvestigated. To investigate the clinical significance of vascular endothelial growth factor receptor-2 (VEGFR2) and programmed death ligand-1 (PD-L1) in osteosarcoma, we analyzes their expression levels in 93 osteosarcoma specimens by immunohistochemistry. Meanwhile, we analyzes their correlation with the metastatic behavior and overall survival (OS). We also investigate the effects of Apatinib on migration and invasion of osteosarcoma cells and its underlying mechanism in vitro and in vivo. In our study, the positive rates of the VEGFR2 and PD-L1 expression are 64.5% (60/93) and 35.5% (33/93), respectively. A significant correlation is detected between VEGFR2 and PD-L1 expression (P = 0.009). Receiver-operating characteristic (ROC) curves analysis indicates the predictive value of the two markers in tumor metastasis, and both PD-L1 and VEGFR2 are negatively correlated with OS. Transwell assays reveals that VEGFR2 inhibition attenuates migration and invasion of osteosarcoma cells. Mechanistically, we demonstrate that Apatinib attenuates migration and invasion by suppressing epithelial-mesenchymal transition (EMT) and inactivating STAT3. Additionally, Apatinib reduces PD-L1 expression in osteosarcoma cells. Apatinib markedly weakens pulmonary metastatic potential of osteosarcoma in vivo. In conclusion, our study reveals a pro-metastatic functional mechanism for VEGFR2 in osteosarcoma. Furthermore, we demonstrate that Apatinib exerts anti-tumor effect not only through antiangiogenic effect, but also via suppressing immune escape, which may represent a potential therapeutic target for metastatic osteosarcoma.

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TGF-β-induced epithelial to mesenchymal transition
Xu, J., Lamouille, S., & Derynck, R. (2009) · Cell Research · doi:10.1038/cr.2009.5 · Cited by 2,804 · see citing works
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8 <sup>+</sup> T lymphocytes are prognostic factors of human ovarian cancer
Hamanishi, J., Mandai, M., Iwasaki, M., Okazaki, T., Tanaka, Y., Yamaguchi, K., Higuchi, T., Yagi, H., Takakura, K., Minato, N., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611533104 · Cited by 1,378 · see citing works
Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial
Judson, I. R., Verweij, J., Gelderblom, H. A. J., Hartmann, J. T., Schöffski, P., Blay, J., Kerst, J. M., Šufliarský, J., Whelan, J. S., Hohenberger, P., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70063-4 · Cited by 1,185 · see citing works
Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer
Nomi, T., Sho, M., Akahori, T., Hamada, K., Kubo, A., Kanehiro, H., Nakamura, S., Enomoto, K., Yagita, H., Azuma, M., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2746 · Cited by 889 · see citing works
Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma
Gao, Q., Wang, X., Qiu, S., Yamato, I., Sho, M., Nakajima, Y., Zhou, J., Li, B., Shi, Y., Xiao, Y., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1608 · Cited by 810 · see citing works
Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma
Hino, R., Kabashima, K., Kato, Y., Yagi, H., Nakamura, M., Honjo, T., Okazaki, T., & TOKURA, Y. (2010) · Cancer · doi:10.1002/cncr.24899 · Cited by 668 · see citing works
Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)
Kempf-Bielack, B., Bielack, S. S., Jürgens, H., Branscheid, D., Berdel, W. E., Exner, G. U., Göbel, U., Helmke, K., Jundt, G., Kabisch, H., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.063 · Cited by 643 · see citing works
Apatinib for Chemotherapy-Refractory Advanced Metastatic Gastric Cancer: Results From a Randomized, Placebo-Controlled, Parallel-Arm, Phase II Trial
Li, J., Qin, S., Xu, J., Guo, W., Xiong, J., Bai, Y., Sun, G., Yang, Y. F., Wang, L., Xu, N., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.48.8585 · Cited by 529 · see citing works
Epithelial–Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma
Lou, Y., Diao, L., Parra, E. R., Denning, W. L., Chen, L., Fan, Y. H., Byers, L. A., Wang, J., Papadimitrakopoulou, V. A., Behrens, C., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1434 · Cited by 439 · see citing works
Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma
Clark, C. A., Gupta, H. B., Sareddy, G. R., Pandeswara, S., Lao, S., Yuan, B., Drerup, J. M., Padron, A. S., Conejo-Garcia, J. R., Murthy, K., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0258 · Cited by 394 · see citing works
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Liu, K., Ren, T., Huang, Y., Sun, K., Bao, X., Wang, S., Zheng, B., & Guo, W. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.422 · Cited by 266 · see citing works
The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC
Manegold, C., Dingemans, A. C., Gray, J. E., Nakagawa, K., Nicolson, M. C., Peters, S., Reck, M., Wu, Y.-L. L. C., Brustugun, O. T., Crinò, L., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.10.003 · Cited by 239 · see citing works
Multicenter phase II study of Apatinib in non-triple-negative metastatic breast cancer
Hu, X., Cao, J., Hu, W., Wu, C., Pan, Y., Cai, L., Tong, Z., Wang, S., Li, J., Wang, Z., et al. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-820 · Cited by 225 · see citing works
PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung
Kim, S., Koh, J., Kim, M., Kwon, D., Go, H., Kim, Y. A., Jeon, Y. K., & Chung, D. H. (2016) · Human Pathology · doi:10.1016/j.humpath.2016.07.007 · Cited by 166 · see citing works
Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma
Peng, H., Zhang, Q., Li, J., Zhang, N., Hua, Y., Xu, L., Deng, Y., Lai, J., Peng, Z., Peng, B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7948 · Cited by 141 · see citing works
B7-H1 Overexpression Regulates Epithelial–Mesenchymal Transition and Accelerates Carcinogenesis in Skin
Cao, Y., Zhang, L., Kamimura, Y., Ritprajak, P., Hashiguchi, M., Hirose, S., & Azuma, M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-2217 · Cited by 94 · see citing works
EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance
Sevelda, F., Mayr, L., Kubista, B., Lötsch, D., van Schoonhoven, S., Windhager, R. H., Pirker, C., Micksche, M., & Berger, W. (2015) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-015-0251-5 · Cited by 73 · see citing works
Knockdown of CMTM3 promotes metastasis of gastric cancer via the STAT3/Twist1/EMT signaling pathway
Yuan, W., Li, T., Mo, X., Wang, X., Liu, B., Wang, W., Su, Y., Xu, L., & Han, W. (2016) · Oncotarget · doi:10.18632/oncotarget.8789 · Cited by 58 · see citing works
Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion
Nagao‐Kitamoto, H., Setoguchi, T., Kitamoto, S., Nakamura, S., Tsuru, A., Nagata, M., Nagano, S., Ishidou, Y., Yokouchi, M., Kitajima, S., et al. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.10.042 · Cited by 55 · see citing works
Mesenchymal to epithelial transition in sarcomas
Yang, J., Du, X., Wang, G., Sun, Y. K., Chen, K., Zhu, X., Lazar, A. J., Hunt, K. K., Pollock, R. E., & Zhang, W. (2013) · European Journal of Cancer · doi:10.1016/j.ejca.2013.11.006 · Cited by 52 · see citing works
Human Chondrosarcoma Cells Acquire an Epithelial-Like Gene Expression Pattern via an Epigenetic Switch: Evidence for Mesenchymal-Epithelial Transition during Sarcomagenesis
Fitzgerald, M. P., Gourronc, F. A., Teoh-Fitzgerald, M. L. T., Provenzano, M. J., Case, A. J., Martin, J. A., & Domann, F. E. (2011) · Sarcoma · doi:10.1155/2011/598218 · Cited by 41 · see citing works
Apatinib ameliorates doxorubicin-induced migration and cancer stemness of osteosarcoma cells by inhibiting Sox2 via STAT3 signalling
Tian, Z., Wang, J. Q., & Ge, H. (2019) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2019.07.003 · Cited by 34 · see citing works
Targeting the MET pathway for potential treatment of NSCLC
Li, A., Gao, H., & Wu, Y.-L. L. C. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.995093 · Cited by 22 · see citing works
Induction of the mesenchymal to epithelial transition by demethylation-activated microRNA-125b is involved in the anti-migration/invasion effects of arsenic trioxide on human chondrosarcoma
Bao, X., Ren, T., Huang, Y., Wang, S., Zhang, F., Liu, K., Zheng, B., & Guo, W. (2016) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-016-0407-y · Cited by 22 · see citing works
Interleukin-22 attenuates double-stranded RNA-induced upregulation of PD-L1 in airway epithelial cells via a STAT3-dependent mechanism
Seki, N., Kan‐o, K., Matsumoto, K., Fukuyama, S., Hamano, S., Tonai, K., Ota, K., Inoue, H., & Nakanishi, Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.10.045 · Cited by 12 · see citing works

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The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem
Corre, I., Verrecchia, F., Crenn, V., Rédiní, F., & Trichet, V. (2020) · Cells · doi:10.3390/cells9040976 · Cited by 475 · see citing works
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Zhao, S., Ren, S., Jiang, T., Zhu, B., Li, X., Zhao, C., Jia, Y., Shi, J., Zhang, L., Liu, X., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0640 · Cited by 320 · see citing works
Immunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer
Xie, C., Zhou, X., Liang, C., Li, X., Ge, M., Chen, Y., Yin, J. J., Zhu, J., & Zhong, C. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02069-4 · Cited by 203 · see citing works
Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment
Petroni, G., Buqué, A., Coussens, L. M., & Galluzzi, L. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00415-5 · Cited by 162 · see citing works
STAT3 and its targeting inhibitors in osteosarcoma
Liu, Y., Liao, S., Bennett, S., Tang, H., Song, D., Wood, D., Zhan, X., & Xu, J. (2020) · Cell Proliferation · doi:10.1111/cpr.12974 · Cited by 159 · see citing works
Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial
Xie, L., Xu, J., Sun, X., Guo, W., Gu, J., Liu, K., Zheng, B., Ren, T., Huang, Y., Tang, X., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000798 · Cited by 145 · see citing works
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Harris, M. A., & Hawkins, C. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073817 · Cited by 143 · see citing works
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Yang, W., Tang, F., Tu, C., Hornicek, F. J., Duan, Z., & Min, L. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215887 · Cited by 107 · see citing works
Targeting STAT3 in cancer and autoimmune diseases
Gharibi, T., Babaloo, Z., Hosseini, A., Abdollahpour‐Alitappeh, M., Hashemi, V., Marofi, F., Nejati‐Koshki, K., & Baradaran, B. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173107 · Cited by 103 · see citing works
Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma
Anand, N., Peh, K. H., & Kolesar, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032858 · Cited by 91 · see citing works
Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?
Tian, Z., Niu, X., & Yao, W. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01642 · Cited by 87 · see citing works
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Rosenbaum, S. R., Knecht, M., Mollaee, M., Zhong, Z., Erkes, D. A., McCue, P. A., Chervoneva, I., Berger, A. C., Lo, J. A., Fisher, D. E., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.036 · Cited by 85 · see citing works
RETRACTED: Codelivery of STAT3 and PD-L1 siRNA by hyaluronate-TAT trimethyl/thiolated chitosan nanoparticles suppresses cancer progression in tumor-bearing mice
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Retracted
An overview of resistance to chemotherapy in osteosarcoma and future perspectives
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Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways
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Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway
Tremblay-LeMay, R., Rastgoo, N., & Chang, H. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0589-1 · Cited by 69 · see citing works
Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies
Ji, Z., Shen, J., Lan, Y., Yi, Q., & Liu, H. (2023) · MedComm · doi:10.1002/mco2.308 · Cited by 68 · see citing works
An update on emerging drugs in osteosarcoma: towards tailored therapies?
Hattinger, C. M., Patrizio, M. P., Magagnoli, F., Luppi, S., & Serra, M. (2019) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2019.1654455 · Cited by 66 · see citing works
Targeting the VEGF Pathway in Osteosarcoma
Assi, T., Watson, S., Samra, B., Rassy, E., Cesne, A. L., Italiano, A., & Mir, O. (2021) · Cells · doi:10.3390/cells10051240 · Cited by 62 · see citing works
Cold Atmospheric Plasma: A New Strategy Based Primarily on Oxidative Stress for Osteosarcoma Therapy
Mateu‐Sanz, M., Tornín, J., Ginebra, M., & Canal, C. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040893 · Cited by 57 · see citing works
Underlying mechanisms and drug intervention strategies for the tumour microenvironment
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Atezolizumab and Bevacizumab Attenuate Cisplatin Resistant Ovarian Cancer Cells Progression Synergistically via Suppressing Epithelial-Mesenchymal Transition
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Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself
Yang, Q., Chen, T., Wang, S., Zhang, X., & Yao, Z. (2020) · Angiogenesis · doi:10.1007/s10456-020-09716-y · Cited by 48 · see citing works
Stabilizing Tumor-Resident Mast Cells Restores T-Cell Infiltration and Sensitizes Sarcomas to PD-L1 Inhibition
Panagi, M., Mpekris, F., Voutouri, C., Hadjigeorgiou, A. G., Symeonidou, C., Porfyriou, E., Michael, C., Stylianou, A., Martin, J. D., Cabral, H., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-0246 · Cited by 44 · see citing works
Phase II trial of VEGFR2 inhibitor apatinib for metastatic sarcoma: focus on efficacy and safety
Liao, Z., Li, F., Zhang, C., Zhu, L., Shi, Y., Zhao, G., Bai, X., Hassan, S., Liu, X., Li, T., et al. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0221-7 · Cited by 41 · see citing works
Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas
Albarrán, V., Villamayor, M. L., Chamorro, J., Rosero, D. I., Pozas, J., Román, M. S., Calvo, J. C., de Aguado, P. P., Moreno, J. A., Guerrero, P., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213784 · Cited by 37 · see citing works
Apatinib ameliorates doxorubicin-induced migration and cancer stemness of osteosarcoma cells by inhibiting Sox2 via STAT3 signalling
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Zheng, B., Zhou, C., Qu, G., Ren, C., Peng, Y., Guo, W., & Yue, B. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.543562 · Cited by 34 · see citing works
Involvement of extracellular vesicles in the macrophage-tumor cell communication in head and neck squamous cell carcinoma
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Apatinib suppresses the migration, invasion and angiogenesis of hepatocellular carcinoma cells by blocking VEGF and PI3K/AKT signaling pathways
Song, J., Guan, Z., Song, C., Li, M., Gao, Z., & Zhao, Y. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12068 · Cited by 32 · see citing works
Current progress and open challenges for applying tyrosine kinase inhibitors in osteosarcoma
Chen, C., Shi, Q., Xu, J., Ren, T., Huang, Y., & Guo, W. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01252-6 · Cited by 29 · see citing works
Adverse events and management of apatinib in patients with advanced or metastatic cancers: A review
Shao, F., Zhang, H., Yang, X., Luo, X., & Liu, J. (2020) · Neoplasma · doi:10.4149/neo_2020_190801n701 · Cited by 30 · see citing works
Advances and challenges in the treatment of osteosarcoma
Wang, X., Zhu, K., Hu, J., & Zhang, C. (2025) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2025.07.001 · Cited by 31 · see citing works
Regulation of the Epithelial to Mesenchymal Transition in Osteosarcoma
Hinton, K., Kirk, A., Paul, P., & Persad, S. (2023) · Biomolecules · doi:10.3390/biom13020398 · Cited by 27 · see citing works
In vivo self-assembly and delivery of VEGFR2 siRNA-encapsulated small extracellular vesicles for lung metastatic osteosarcoma therapy
Yu, L., Fan, G., Wang, Q., Zhu, Y., Zhu, H., Chang, J., Wang, Z., Zhan, S., Hua, X., She, D., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06159-3 · Cited by 28 · see citing works
Big data-driven precision medicine: Starting the custom-made era of iatrology
Song, C. M., Kong, Y., Huang, L., Luo, H., & Zhu, X. M. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110445 · Cited by 26 · see citing works
The Sarcoma Immune Landscape: Emerging Challenges, Prognostic Significance and Prospective Impact for Immunotherapy Approaches
Koumarianou, A. A., & Durán, J. (2021) · Cancers · doi:10.3390/cancers13030363 · Cited by 26 · see citing works
Tyrosine kinase inhibitors in sarcoma treatment (Review)
Kyriazoglou, A. I., Gkaralea, L. E., Kotsantis, I., Anastasiou, Μ., Pantazopoulos, A., Prevezanou, M., Chatzidakis, I., Kavourakis, G., Economopoulou, P., Nixon, I., et al. (2022) · Oncology Letters · doi:10.3892/ol.2022.13303 · Cited by 25 · see citing works
Efficacy and safety of apatinib in treatment of osteosarcoma after failed standard multimodal therapy
Tian, Z., Gu, Z., Wang, X., Liu, Z., Yao, W., Wang, J., Zhang, P., Cai, Q., & Ge, H. (2019) · Medicine · doi:10.1097/md.0000000000015650 · Cited by 23 · see citing works
Apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer via the Akt/β-catenin pathway
Wei, B., Wang, Y., Wang, J., Cai, X., Xu, L., Wu, J., Wang, Y., Liu, W., Gu, Y., Guo, W., et al. (2020) · Cancer Cell International · doi:10.1186/s12935-020-01290-z · Cited by 23 · see citing works
Apatinib plus ifosfamide and etoposide for relapsed or refractory osteosarcoma: A retrospective study in two centres
Xie, L., Xu, J., Sun, X., Li, X., Liu, K., Liang, X., Zhou, Z., Zhuang, H., Sun, K., Wu, Y., et al. (2021) · Oncology Letters · doi:10.3892/ol.2021.12813 · Cited by 19 · see citing works
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Apatinib as targeted therapy for sarcoma
Li, F., Liao, Z., Zhang, C., Zhao, J. L., Xing, R., Teng, S., Zhang, J., Yang, Y., & Yang, J. (2018) · Oncotarget · doi:10.18632/oncotarget.24647 · Cited by 20 · see citing works
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Liu, X., Xu, J., Li, F., Liao, Z., Ren, Z., Zhu, L., Shi, Y., Zhao, G., Bai, X., Zhao, J. L., et al. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109587 · Cited by 20 · see citing works
Prognostic Value of Programmed Cell Death 1 Ligand-1 in Patients With Bone and Soft Tissue Sarcomas: A Systemic and Comprehensive Meta-Analysis Based on 3,680 Patients
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Efficacy and safety of apatinib in the treatment of osteosarcoma: a single-arm meta-analysis among Chinese patients
Yao, H., Chen, X., & Tan, X. (2021) · BMC Cancer · doi:10.1186/s12885-021-08154-3 · Cited by 19 · see citing works
Chloroquine suppresses proliferation and invasion and induces apoptosis of osteosarcoma cells associated with inhibition of phosphorylation of STAT3
Chen, C., Zhang, H., Yu, Y., Huang, Q., Wang, W., Niu, J., Lou, J., Ren, T., Huang, Y., & Guo, W. (2021) · Aging · doi:10.18632/aging.203196 · Cited by 18 · see citing works
Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer
Liang, L.-J., Hu, C., Wen, Y., Geng, X.-W., Chen, T., Gu, G.-Q., Wang, L., Xia, Y., Liu, Y., Fei, J., et al. (2019) · Cancer Research and Treatment · doi:10.4143/crt.2019.296 · Cited by 17 · see citing works
The efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis
Liu, J.-Y., Zhu, B., Wang, Y., & Sun, X. (2020) · International Journal of Clinical Oncology · doi:10.1007/s10147-020-01644-7 · Cited by 17 · see citing works
LRP8 activates STAT3 to induce PD-L1 expression in osteosarcoma
Zheng, S., Wei, Y., Jiang, Y., & Hao, Y. (2020) · Tumori Journal · doi:10.1177/0300891620952872 · Cited by 15 · see citing works
Neoadjuvant PD-1 Inhibitor Plus Apatinib and Chemotherapy Versus Apatinib Plus Chemotherapy in Treating Patients With Locally Advanced Gastric Cancer: A Prospective, Cohort Study
Wang, C., Wang, Z., Zhao, Y., & Wang, F. (2023) · Journal of the Korean Gastric Cancer Association · doi:10.5230/jgc.2023.23.e17 · Cited by 13 · see citing works
Apatinib inhibits tumour progression and promotes antitumour efficacy of cytotoxic drugs in oesophageal squamous cell carcinoma
Chi, Y., Wang, F., Zhang, Y., Shan, Z., Tao, W., Lian, Y., Xin, D., Fan, Q., & Sun, Y. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17209 · Cited by 13 · see citing works
Apatinib inhibits cell proliferation and migration of osteosarcoma via activating LINC00261/miR-620/PTEN axis
Han, G., Guo, Q., Ma, N., Bi, W., Xu, M. M., & Jia, J. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1949132 · Cited by 12 · see citing works
Retracted: LINC00657 activates PD‐L1 to promote osteosarcoma metastasis via miR‐106a
Zhang, J., Chou, X., Zhuang, M., Zhu, C., Hu, Y., Cheng, D., & Liu, Z. (2020) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29574 · Cited by 12 · see citing works
Retracted
Effective Treatment of Low-Grade Myofibroblastic Sarcoma with Apatinib: A Case Report and Literature Review
Lin, Y., Gao, X. H., Liu, Z., Liu, Z., Li, Y., Liang, R., Liao, Z., & Ye, J. (2022) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s359492 · Cited by 12 · see citing works
Radiotherapy with apatinib for recurrence of malignant phyllodes tumor of the breast
Wu, H., Li, L., Yang, J., Chen, G., Zhang, W., & Wang, H. (2020) · Medicine · doi:10.1097/md.0000000000018808 · Cited by 12 · see citing works
Signal Pathways and microRNAs in Osteosarcoma Growth and the Dual Role of Mesenchymal Stem Cells in Oncogenesis
Тодосенко, Н. М., Хлусов, И. А., Yurova, K. A., Геннадьевна, Х. О., & Litvinova, L. S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108993 · Cited by 12 · see citing works
PD-L1 Expression Correlated with Clinicopathological Factors and Akt/Stat3 Pathway in Oral SCC
Geum, D., Hwang, D., Lee, C. H., Cho, S., Jang, M., Ryu, M. H., & Kim, U. (2022) · Life · doi:10.3390/life12020238 · Cited by 11 · see citing works
Immune checkpoint blockade therapies for HCC: current status and future implications
Shrestha, R., Bridle, K. R., Crawford, D. H., & Jayachandran, A. (2019) · Hepatoma Research · doi:10.20517/2394-5079.2019.24 · Cited by 10 · see citing works
Pseudogene MSTO2P enhances hypoxia-induced osteosarcoma malignancy by upregulating PD-L1
Shi, C., Huang, C.-M., Wang, B., Sun, T.-F., Zhu, A., & Zhu, Y.-C. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.07.113 · Cited by 10 · see citing works
Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?
van Oost, S., Meijer, D. M., Kuijjer, M. L., Bovée, J. V. M. G., & de Miranda, N. F. C. C. (2021) · Biomedicines · doi:10.3390/biomedicines9081048 · Cited by 9 · see citing works
Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
Cui, L., Yan, L., Guan, X., Dong, B., Zhao, M., Lv, A., Liu, D.-N., Wang, Z., Liu, F., Wu, J., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.739139 · Cited by 9 · see citing works
Phase II study of apatinib combined with temozolomide in patients with advanced melanoma after failure of immunotherapy
Zhou, L., Yang, Y., Si, L., Chi, Z., Sheng, X., Lian, B., Wang, X., Tang, B., Mao, L., Yan, X., et al. (2022) · Melanoma Research · doi:10.1097/cmr.0000000000000809 · Cited by 8 · see citing works
WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway
Xia, Y., Chang, X., Lian, S., & Wei, Z. (2018) · Journal of International Medical Research · doi:10.1177/0300060518778905 · Cited by 7 · see citing works
Effects of Apatinib combined with Temozolomide on levels of sPD-1 and sPD-L1 in patients with drug-resistant recurrent glioblastoma
Kuang, R. Z., Wang, J., Wang, Y., & Tang, X. P. (2024) · Clinics · doi:10.1016/j.clinsp.2024.100376 · Cited by 5 · see citing works
Lycorine combined with cisplatin synergistically inhibited osteosarcoma cells growth and metastasis by suppressing Wnt/β-Catenin and STAT3 signaling pathways
Liu, X., Ye, C., Feng, J. Y., Zhan, P., Luo, Q., & Liu, J. (2024) · Journal of Functional Foods · doi:10.1016/j.jff.2024.106339 · Cited by 4 · see citing works
The Safety and Efficacy of Camrelizumab and Its Combination With Apatinib in Various Solid Cancers
Wang, K., Li, B., Li, M., Li, S., Yang, H. J., & Yuan, L. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.568477 · Cited by 4 · see citing works
Exploring Natural Compounds Targeting PD-L1 and STAT3: Toxicogenomic Analysis, Virtual Screening, Molecular Docking, ADMET Evaluation, and Biological Activity Prediction
Karakuş, F., Kuzu, B., Köstekci, S., & Tülüce, Y. (2024) · Current Computer - Aided Drug Design · doi:10.2174/0115734099307259240522093710 · Cited by 4 · see citing works
A study protocol for an open‐label, single‐arm, single‐center phase I clinical study on tolerability, safety, and efficacy of dalpiciclib combined with apatinib in the treatment of patients with advanced or metastatic sarcoma
Huang, H., Zhang, H., & Cao, B. (2024) · Thoracic Cancer · doi:10.1111/1759-7714.15208 · Cited by 4 · see citing works
Epithelial–Mesenchymal Transition in Osteosarcoma as a Key Driver of Pulmonary Metastasis
Luo, F., Ando, K., Takemura, Y., Park, T.-H., Yayama, T., & Imai, S. (2025) · Cancers · doi:10.3390/cancers17172922 · Cited by 3 · see citing works
Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non–small cell lung cancer
Nakahama, K., Kaneda, H., Osawa, M., Fukui, M., Izumi, M., Yoshimoto, N., Sugimoto, A. K., Nagamine, H., Ogawa, K., Matsumoto, Y., et al. (2022) · Cancer Science · doi:10.1111/cas.15464 · Cited by 3 · see citing works
Apatinib plus chemotherapy for non-metastatic osteosarcoma: a retrospective cohort study
Wang, J., Zhang, F., Dong, S., Yang, Y., Gao, F., Liu, G., Zhang, P., Wang, X., Du, X., & Tian, Z. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1227461 · Cited by 2 · see citing works
Anlotinib combined with penpulimab in the treatment of advanced adult thoracic spinal osteosarcoma: a case report
Chen, X., Li, X., Zhao, H., Qu, J., Li, X., Lin, C., & Yuan, Z. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1599496 · Cited by 2 · see citing works
Apatinib inhibits the proliferation of gastric cancer cells via the AKT/GSK signaling pathway in vivo
Chen, Y., Chen, N., Xu, J., Wang, X., Wei, X., Tang, C., Duanmu, Z., & Shi, J. (2021) · Aging · doi:10.18632/aging.203458 · Cited by 2 · see citing works
Clinical Research Progress of Apatinib in the Treatment of Hepatocellular Carcinoma
冯, 源. (2021) · Advances in Clinical Medicine · doi:10.12677/acm.2021.1112919 · Cited by 1 · see citing works
Apatinib Suppressed Macrophage-Mediated Malignant Behavior of Hepatocellular Carcinoma Cells via Modulation of VEGFR2/STAT3/PD-L1 Signaling
Yin, T., Fu, C. B., Wu, D. D., Nie, L., Chen, H., & Wang, Y. (2023) · Molecular Biology · doi:10.1134/s0026893323040180 · Cited by 1 · see citing works
[Effect of Apatinib on Invasion and Migration of Lung Cancer Cells and Its Mechanism].
Yin, Y., Gong, H., Li, Y., Zhang, H., Li, Y., Li, W., Wang, P., Shi, R., Liu, H., & Chen, J. (2019) · PubMed Central · doi:10.3779/j.issn.1009-3419.2019.05.02 · Cited by 1 · see citing works
The Complex Nature of Soft Tissue Sarcomas, Including Retroperitoneal Sarcomas
Grizzi, F., Borroni, E. M., Qehajaj, D., Štifter, S., Chiriva‐Internati, M., & Cananzi, F. (2018) · Updates in surgery/Updates in surgery series · doi:10.1007/978-88-470-3980-3_3
Prognostic and Clinicopathological Significance of Programmed Death-Ligand 1 in Osteosarcoma: a Meta-Analysis
Gu, X. (2019) · Clinical surgery research communications · doi:10.31491/csrc.2019.06.031
Case reports with durable therapeutic effects from the prospective phase 2 trial
Xie, L., Xu, J. H., Sun, X., Tang, X., Sun, K., Li, Y., & Guo, W. (2020) · Medicine Case Reports and Study Protocols · doi:10.1097/md9.0000000000000010
A VEGFR2 Antagonist Inhibits Cell Proliferation, Migration, and Invasion by Blocking the PI3K-Akt and MAPK Signaling Pathways in Thyroid CancerPreprint
Liu, C., Liu, Z., Zhao, H., Cao, Y., Lin, Y., & Li, X. (2021) · Research Square · doi:10.21203/rs.3.rs-625662/v1
Apatinib Suppressed Macrophage-Mediated Malignant Behavior of Hepatocellular Carcinoma Cells via Modulation of VEGFR2/STAT3/PD-L1 Signaling
Yin, T., Fu, C. B., Wu, D., Nie, L., Chen, H., & Wang, Y. (2023) · Molecular Biology · doi:10.31857/s0026898423040237
Anlotinib/Apatinib Plus Chemotherapy as Second-Line or Later Therapy in Advanced OsteosarcomaPreprint
Song, H., Han, K., Yang, Y., Sun, X., Zhou, M., Tian, C., Zhu, H., Chen, Q., Min, D., & Li, B. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4880343
Endophytic fungi in anticancer drug development: Targeting tumor microenvironment
Kumar, Y., Gambhir, L., Sharma, G., Sharma, A., & Kapoor, N. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-31484-1.00004-9
Significant increase in calcification and ossification observed after the second relapse of low-grade myofibroblast sarcoma treated with radiotherapy followed by anlotinib and toripalimab: a case report
Lang, J., & Xiong, Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1606825
Additional file 1 of Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer
Xie, C., Zhou, X., Liang, C., Li, X., Ge, M., Chen, Y., Yin, J., Zhu, J., & Zhong, C. (2021) · Figshare · doi:10.6084/m9.figshare.16436002
Progression-free survival 3 of 22 months achieved through third-line therapy with adebrelimab in patient with recurrent chordoma: a case report
Sun, L., Lang, J., Zhang, W., & Xiong, Z. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1850680

VEGFR2 Promotes Metastasis and PD-L2 Expression of Human Osteosarcoma Cells by Activating the STAT3 and RhoA-ROCK-LIMK2 Pathways
Zheng, B., Zhou, C., Qu, G., Ren, C., Peng, Y., Guo, W., & Yue, B. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.543562 · Cited by 34 · see citing works
Sunitinib inhibits PD-L1 expression in osteosarcoma by targeting STAT3 and remodels the immune system in tumor-bearing mice
Duan, X. L., Guo, J. P., Li, F., Xiu, C., & Wang, H. (2020) · Future Oncology · doi:10.2217/fon-2019-0725 · Cited by 30 · see citing works
743P A comparison of the histopathological response of cisplatin-adriamycin-methotrexate versus cisplatin- adriamycin as a neoadjuvant chemotherapy in cases of primary non metastatic osteosarcoma in Indian population
Dubey, S. (2024) · Annals of Oncology · doi:10.1016/j.annonc.2024.10.776
The combination of apatinib and antigen-specific DC-induced T cells exert antitumor effects by potently improving the immune microenvironment of osteosarcoma
Hu, T., Sun, W., Jin, Y., Dong, Y., Liu, W., Sun, Z., Xiang, Y., & Chen, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e36016 · Cited by 4 · see citing works
Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma
Liu, K., Ren, T., Huang, Y., Sun, K., Bao, X., Wang, S., Zheng, B., & Guo, W. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.422 · Cited by 266 · see citing works

Authors: Zheng, B., Ren, T., Huang, Y., & Guo, W.
Affiliations: Peking University People's Hospital (CN)
Corresponding author: Guo, Wei
ORCID: Zheng, Bingxin
Ren, Tingting
Huang, Yi
Guo, Wei
Venue: Biochemical and Biophysical Research Communications
Publisher: Elsevier BV
Published: 2018-01
Volume: 495
Issue: 2
Pages: 1695-1701
ISSN: 0006-291X (ISSN-L)
DOI: 10.1016/j.bbrc.2017.12.032
OpenAlex: W2773643761
Cited by: 89
References: 25
Citations by year: 2026: 1 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 16 · 2020: 22 · 2019: 13 · 2018: 4
FWCI: 8.82
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Biochemical and Biophysical Research Communications (publishedVersion)
PubMed (publishedVersion)
Funders: National Natural Science Foundation of China (81572633, 81472509)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: apatinib, osteosarcoma, VEGFR2, PD-L1, STAT3, metastasis, cell migration and invasion, epithelial-mesenchymal transition, anti-angiogenic therapy, immune evasion, lung metastasis, overall survival, predictive biomarkers
MeSH terms: Animals, Antineoplastic Agents, Bone Neoplasms, Cell Movement, Female, Humans, Immunohistochemistry, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Neoplasm Invasiveness, Pyridines, Osteosarcoma, Biomarkers, Tumor, Xenograft Model Antitumor Assays, Vascular Endothelial Growth Factor Receptor-2, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Epithelial-Mesenchymal Transition, B7-H1 Antigen

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Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3

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