Abstract
BackgroundLiposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. Therefore, the development of advanced treatment strategies for LPS is required. In the present study, we investigated the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor on cell viability and apoptosis in LPS and DDLPS cell lines of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor.MethodsWe analyzed cell viability after treatment with TRAIL and a c-Met inhibitor by measuring CCK8 and death receptor 5 (DR5) expression levels via fluorescence activated cell sorting (FACS) in both sarcoma cell lines and DDLPS patient-derived cells (PDCs). Moreover, we validated the effects of TRAIL alone and in combination with c-Met inhibitor on apoptosis in LPS cell lines and DDLPS PDCs via FACS.ResultsOur results revealed that combination treatment with a c-Met inhibitor and human recombinant TRAIL (rhTRAIL) suppressed cell viability and induced cell death in both sarcoma cell lines and DDLPS PDCs, which showed varying sensitivities to rhTRAIL alone. Also, we confirmed that treatment with a c-Met inhibitor upregulated DR5 levels in sarcoma cell lines and DDLPS PDCs. In both TRAIL-susceptible and TRAIL-resistant cells subjected to combination treatment, promotion of apoptosis was dependent on DR5 upregulation.ConclusionFrom these results, our findings validated that DR5 up-regulation caused by combination therapy with a c-Met inhibitor and rhTRAIL enhanced TRAIL sensitization and promoted apoptosis. We propose the use of this approach to overcome TRAIL resistance and serve as a novel treatment strategy for clinical trials.
Highlights
Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas
MFHino and SW872 cells were found to be highly sensitive to low doses of rhTRAIL, whereas HT1080 cells showed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance approaching that of normal control cells and Adipose tissue derived mesenchymal stem cell (ADMSC), even under high rhTRAIL doses (Fig. 1: Additional file 1: Table S1)
C-met inhibitors combined with rhTRAIL enhanced cell death in sarcoma cell lines To determine whether c-Met inhibitors enhanced sensitivity to TRAIL in sarcoma cell lines, malignant fibrous histocytoma (MFH)-ino cells were treated with increasing doses of one of two c-Met inhibitors, PHA or PF, in combination with rhTRAIL
Summary
Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. The most prevalent subtypes of STS include liposarcoma (LPS), undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma (LMS), and gastrointestinal stromal tissue (GIST). DDLPS is more aggressive, has a higher rate of mitosis and proliferation and is characterized by a high frequency of recurrence and metastasis. DDLPS, which mainly develops in the retroperitoneum, is highly aggressive, and often exhibits resistance to chemotherapy and radiotherapy treatments; as a result, patients with DDLPS have a poor prognosis after surgical resection of these tumors [4]. DDLPS remains one of the most challenging cancers to treat, and further studies are required to develop targeted therapies that can effectively overcome the drug resistance often associated with these tumors
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