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

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.

• Authors: Bingxin Zheng, Tingting Ren, Yi Huang, Wei Guo
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 495 Issue 2 Pg. 1695-1701 (01 08 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29225166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Pyridines
• STAT3 Transcription Factor
• STAT3 protein, human
• apatinib
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• B7-H1 Antigen (metabolism)
• Biomarkers, Tumor (antagonists & inhibitors, metabolism)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Humans
• Immunohistochemistry
• Lung Neoplasms (prevention & control, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness (prevention & control)
• Osteosarcoma (drug therapy, metabolism, pathology)
• Pyridines (pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays