Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

Abstract

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.

Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer

“… 37 The RRM2/PI3K/Akt signal pathway also exists in liposarcoma cells. 38 Intriguingly, they also showed that, in RRM2-silenced MDA-MB-231 cells, PI3K/Akt pathway agonist IGF1 restores the Akt phosphorylation level. It seems that PI3K/Akt pathway can be regulated both by IGF1/IGF1R and RRM2.…”

Establishment and evaluation of retroperitoneal liposarcoma patient-derived xenograft models: an ideal model for preclinical study

“…The PDX models would benefit preclinical studies of treatments that target tumor vessels, CAFs, and TAMs, and identify the beneficial population by evaluating levels of different microenvironment composition. Relevant to this study, we are currently conducting research on tyrosine kinase inhibitors, a kind of small-molecule anti-angiogenesis drugs, and we have shown that they can inhibit angiogenesis and tumor growth in the RLPS PDX model presented here 37 .…”

The Predictive Role of the Histopathological Scoring System in Adipose Tumors—Lipoma, Atypical Lipomatous Tumor, and Liposarcoma

“…On the other hand, this phenomenon determines the initiation of angiogenesis to form new blood vessels from the already existing ones [30]. Tumor microvascular density (MVD) assessment is an essential method for quantifying angiogenesis [31].…”

“…In their study, MVD was significantly correlated with tumor necrosis, as well as the association with low overall survival. Also, they observed that MVD was an independent risk factor of overall survival [31]. In addition, the study conducted by Virginia Baneth demonstrated that MVD is higher in liposarcomas compared to the other sarcoma included in their study (fibrosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma) [33].…”