EPHB4 tyrosine‐kinase receptor expression and biological significance in soft tissue sarcoma

Abstract

Soft tissue sarcomas (STS) are heterogeneous malignant tumors of mesenchymal origin. Due to low incidence and high number of different histological subtypes, their pathogenesis and thus potential targets for their therapy remain barely investigated. Several studies revealed significant higher EPHB4 expression in malignancies such as prostate and colorectal cancer showing survival advantages for these tumor cells. Therefore we studied the expression of EPHB4 in a total of 46 clinical human specimens of different STS and human fibroblasts. EPHB4 mRNA and protein expression were significantly increased in synovial sarcoma. After targeting EPHB4 in fibrosarcoma, synovial sarcoma, liposarcoma and MFH sarcoma cell lines by siRNA or by inhibition of autophosphorylation using the specific EPHB4 kinase inhibitor NVP-BHG712 a decreased proliferation rate/ vitality of synovial-and fibrosarcoma cells was observed. Silencing of EPHB4 significantly reduced the transmigration of synovial sarcoma cells towards fibroblasts and endothelial cells. In addition, we assessed the anti-metastatic effect of EPHB4 inhibition in vivo by intraperitoneal administration of the EPHB4 inhibitor in an appropriate sarcoma lung metastasis xenograft model. As result 43% of NVP-BHG712 treated mice (n 5 3/7) developed pulmonary metastases whereas all control mice (n 5 5) revealed lung metastases. The residual 57% of mice (n 5 4/7) showed only small local tumor cell spots. Size measurements of the Vimentin positive area explained significant decrease in lung metastasis formation (p < 0.05) after EPHB4 kinase inhibition. In summary, these data provide first evidence of the importance of EPHB4 in the tumorigenesis of synovial sarcoma and present EPHB4 as a potential target in the therapy of this malignancy.

PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma

“…NVP is a small molecule that selectively inhibits tyrosine kinase activity of EphB4 (45). Becerikli et al (46) showed that NVP inhibited EphB4 autophosphorylation, reduced cell growth rate of synovial sarcoma, and fibrosarcoma cells in vitro and hampered sarcoma lung metastasis in vivo. Inhibition of EphB4 by NVP overcomes the acquired resistance to cisplatin in melanoma xenograft models (47).…”

Silencing of COPB2 inhibits the proliferation of gastric cancer cells and induces apoptosis via suppression of the RTK signaling pathway

“…In addition, knockdown of EphA2 expression has been observed to inhibit gastric cancer cell proliferation and invasion in vitro and in vivo (43). An additional study (44) demonstrated that EphB4-targeting siRNA decreases non-small cell lung cancer cell viability and the volume of established tumors in vivo .…”

Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma

“…Many sarcoma subtypes belonging to both these categories show aberration and/or mutation in signal transduction pathways, particularly defects in receptor tyrosine kinase (RTK) signaling [ 34 , 35 ]. Recent evidence suggests involvement of RTKs such as PDGFR [ 29 , 36 , 37 ], c-Met [ 38 ], Axl [ 39 ], IGF1-R [ 40 ], EphB4 [ 41 ] and ErbB4 [ 42 ] as driver kinases in different sarcoma subtypes including synovial sarcoma, Ewing sarcoma as well as malignant peripheral nerve sheath tumor (MPNST). Detailed phosphoproteomic analysis from cell lines and patient tumors also revealed involvement of RTKs such as PDGFR, Eph receptors, Axl, c-Met and IGF1-R [ 9 ] as potential driver kinases in sarcomas.…”