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Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
Lixuan Cui1, Liang Yan1, Xiaoya Guan1
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
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.
Insights
Apatinib and Epirubicin show significant anti-tumor effects against retroperitoneal liposarcoma by inhibiting cell proliferation and tumor growth. This combination therapy targets key molecular pathways, offering a promising treatment for this rare cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Primary retroperitoneal liposarcomas (RLPSs) are rare, aggressive tumors with limited therapeutic options.
- Anti-angiogenic tyrosine kinase inhibitors show promise against solid tumors.
- Investigating novel therapeutic strategies for RLPS is crucial.
Purpose of the Study:
- To evaluate the efficacy of Apatinib against retroperitoneal liposarcoma cells.
- To elucidate the underlying molecular mechanisms of Apatinib's action.
- To explore the combined anti-tumor effects of Apatinib and Epirubicin.
Main Methods:
- Assessed microvessel density (MVD) in RLPS tissues using CD34 staining.
- Utilized cell proliferation, migration, invasion, and apoptosis assays for liposarcoma cells.
- Employed RNA sequencing and western blotting to identify key molecular pathways.
- Established patient-derived tumor xenografts (PDX) in mice to evaluate in vivo efficacy and safety.
Main Results:
- High MVD correlated with poorer survival in RLPS patients.
- Apatinib inhibited liposarcoma cell proliferation, invasion, and migration, while increasing apoptosis and inducing G1 arrest.
- Combined Apatinib and Epirubicin demonstrated enhanced anti-tumor effects.
- Apatinib downregulated TYMS and RRM2, suppressing the TYMS/STAT3/PD-L1 and RRM2/PI3K/AKT/mTOR pathways.
- In vivo studies confirmed Apatinib and combination therapy's ability to inhibit angiogenesis and repress tumor growth.
Conclusions:
- Apatinib, alone and in combination with Epirubicin, exhibits potent in vitro and in vivo anti-tumor activity against liposarcoma.
- Apatinib's mechanism involves inhibiting liposarcoma cell proliferation via the RRM2/PI3K/AKT/mTOR pathway.
- Apatinib may also downregulate PD-L1 expression through the TYMS/STAT3 signaling pathway.
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