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Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c‐MET signaling in SS. Both HGF and c‐MET were highly expressed in Yamato‐SS cells, resulting in activation of c‐MET and its downstream AKT and extracellular signal‐regulated kinase signaling pathways, whereas c‐MET was expressed but not activated in SYO‐1 or HS‐SY‐II cells. c‐MET‐activated Yamato‐SS cells showed higher anchorage‐independent growth ability and less sensitivity to chemotherapeutic agents than did c‐MET‐inactivated SYO‐1 or HS‐SY‐II cells. INC280, a selective c‐MET inhibitor, inhibited growth of Yamato‐SS cells both in vitro and in vivo but not that of SYO‐1 or HS‐SY‐II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c‐MET and its downstream effectors in Yamato‐SS cells. Co‐expression of HGF and c‐MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c‐MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c‐MET‐activated SS. HGF/c‐MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c‐MET inhibitors. HGF/c‐MET signaling is a promising therapeutic target in a subset of patients with SS. Inhibition of this signaling could be a novel strategy in future clinical practice for treatment of refractory SS.

Approximately 60–70% of EWSR1 -negative small blue round cell sarcomas harbour a rearrangement of CIC , most commonly CIC-DUX4 . CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo . Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.

Lactic acid bacteria (LAB) have been widely used as probiotics which contribute to our health. We previously reported that subsp. 2038 and 1131, two yogurt starter strains, ameliorate the intestinal barrier dysfunction caused by tumor necrosis factor (TNF)-α and interferon (IFN)-γ in Caco-2 cells. However, Caco-2 cells differ from living organisms in various ways. We have developed a human induced pluripotent stem cell-derived crypt-villus structural small intestine (hiPSC-SI) was established with a villus-like structure containing constituent cells of the small intestine. A hiPSC-SI and LAB co-culture model was established to assess the impact of LAB on barrier function and elucidate the underlying mechanisms. The medium on the luminal side for co-culturing cells and bacteria was examined and determined to use Hanks' balanced salt solution without glucose in terms of bacterial survival rate. LAB were found to ameliorate permeability and decrease the gene expression of tight junction associated proteins induced by TNF-α and IFN-γ. Regarding cell differentiation, LAB suppressed the downregulation of , , and by cytokines. Moreover, they ameliorated reduced mucin 2 protein production and decreased the number of mucin 2-positive cells. Finally, transcriptome analysis suggested that they ameliorated the aberration in cytokine-induced cell differentiation via an anti-inflammatory effect on intestinal stem cells. The results indicate that LAB ameliorate the cytokine-induced dysfunction of intestinal barrier integrity and homeostasis disrupted by cytokines in a co-culture model of hiPSC-SI and LAB.

BackgroundLow-grade osteosarcomas, namely parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LGCOS), occasionally dedifferentiate into high-grade malignancy, referred to as dedifferentiation in low-grade osteosarcoma (DLOS). This study aimed to elucidate the clinicopathologic features of DLOS, which are poorly described to date due to the extreme rarity of the disease.MethodsA total of 33 patients with DLOS were included. Clinical characteristics, including the diagnostic accuracy of tumor biopsy, multimodal treatments, and clinical course, were retrospectively reviewed. Univariate analysis was performed to identify prognostic factors associated with overall survival (OS) and metastasis-free survival (MFS).ResultsThe tumor subtypes comprised 10 cases (30.3%) of LGCOS and 23 cases (69.7%) of POS. The timing of dedifferentiation was synchronous in 25 (75.8%) and metachronous in 8 (24.2%) patients. The rates of preoperative diagnosis of DLOS were 40.0% and 65.4% for core needle biopsy and incisional biopsy, respectively. All patients underwent surgery and 25 patients received perioperative chemotherapy. Of the 13 patients who received neoadjuvant chemotherapy, 11 exhibited a poor histological response. The 5-year OS and MFS rates were 88.1% and 77.7%, respectively. Univariate analysis revealed that local recurrence was associated with poor OS (P < 0.01) and MFS (P < 0.01). Perioperative chemotherapy did not affect OS or MFS.ConclusionsThe diagnostic accuracy of tumor biopsy for DLOS was lower than that for bone sarcomas, as reported previously. In contrast to conventional osteosarcomas with high chemosensitivity, both histological responses and survival analysis revealed low efficacy of chemotherapy for DLOS.

Background: Retroperitoneal sarcomas are rare neoplasms that occur in the retroperitoneum. Complete surgical resection is the only effective treatment option. The prediction of prognosis by histological diagnosis has not yet been established. The purpose of this study was to identify the usefulness of [18-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging for validating the prognosis of retroperitoneal sarcoma (RPS) established by histological diagnosis. Methods: We retrospectively reviewed 201 patients with RPS treated at the Osaka International Cancer Institute between 2010 and 2021. We extracted the clinical data, including standardized uptake values (SUVs), evaluated with FDG-PET, and statistically analyzed the data. Results: The median age of patients was 64 years (range, 31–85 years). A total of 101 (50.2%) patients were men, and 100 (49.8%) were women. Surgical resection was performed in 155 (77.1%) patients. On histological analysis, 75 (37.3%), 52 (25.9%), and 29 (14.4%) patients were diagnosed with dedifferentiated liposarcoma, well-differentiated liposarcoma, and leiomyosarcoma, respectively. The median survival time for patients with high maximum SUV (SUVmax) (≥4) or low SUVmax (<4) was 275.8 months and 79.5 months, respectively. Furthermore, among the patients with dedifferentiated liposarcoma, the overall survival rate for patients with high SUVmax (≥4) was significantly lower than that of those with low SUVmax (<4). Conclusions: The present study demonstrated that SUVmax calculated with FDG-PET was useful as a prognostic factor in RPS, especially in dedifferentiated liposarcoma and Grade2 RPS. To devise a treatment strategy for RPS, SUVmax during FDG-PET scan may be considered for clinical assessment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background The prognosis of synovial sarcoma (SS), an aggressive soft tissue sarcoma, remains poor. We previously reported that c-MET or platelet-derived growth factor receptor α (PDGFRα) signalling pathway is related to SS progression based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays. TAS-115 is a novel c-MET/ vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitor that has been shown to inhibit multiple RTKs. Here we aimed to investigate the therapeutic potential of TAS-115 against SS. Methods We first evaluated which signalling pathway was relevant to the viability of three human SS cell lines: Yamato-SS, SYO-1 and HS-SY-II. Next, we assessed the anticancer activity and mechanism of action of TAS-115 in these SS cell lines. Finally, we compared the ability of TAS-115 to inhibit c-MET and PDGFRα phosphorylation with that of pazopanib. Results We classified the SS cell lines as c-MET-dependent or PDGFRα-dependent based upon the differences in the signalling pathway relevant for growth and/or survival. We also found that c-MET and PDGFRα were the primary activators of both phosphatidylinositol 3-kinase/AKT and mitogen-activated protein kinase pathways in c-MET-dependent and PDGFRα-dependent SS cells, respectively. TAS-115 treatment blocked the phosphorylation of PDGFRα as well as that of c-MET and their downstream effectors, leading to marked growth inhibition in both types of SS cell lines in in vitro and in vivo studies. Furthermore, PDGFRα phosphorylation, on at least four representative autophosphorylation sites, was impeded by TAS-115 equivalently to pazopanib. Conclusions These experimental results have demonstrated the significance of c-MET and PDGFRα signalling for growth and/or survival of SS tumours. TAS-115 monotherapy may benefit SS patients whose tumours are dependent upon either c-MET or PDGFRα signalling by functioning as a multiple tyrosine kinase inhibitor to suppress c-MET as well as PDGFRα pathways.

Background Epithelioid sarcoma (EpS) is a high-grade malignant soft-tissue sarcoma characterized by local recurrences and distant metastases. Effective treatments for EpS have not been established and thus novel therapeutic approaches against EpS are urgently required. mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors. This reactivation is receptor tyrosine kinase (RTK)-dependent due to a release of negative feedback inhibition. We found that c-MET was the most highly activated RTK in two human EpS cell lines, Asra-EPS and VAESBJ. Here we investigated the functional and therapeutic relevance of mTOR and/or c-MET signaling pathways in EpS both in vitro and in vivo . Methods We first examined the effects of an mTOR inhibitor, RAD001 (everolimus), on cell proliferation, cell cycle, AKT/mTOR signaling, and xenograft tumor growth in EpS cell lines. Next, we determined whether RAD001-induced AKT reactivation was blocked by silencing of c-MET or treatment with a selective c-MET inhibitor, INC280. Finally, we evaluated the antitumor effects of RAD001 combined with INC280 on EpS cell lines compared with either single agent or control in vitro and in vivo . Results Constitutive AKT phosphorylation was observed in Asra-EPS and VAESBJ cells. RAD001 suppressed EpS cell growth by inducing cell cycle arrest but enhanced AKT phosphorylation, which resulted in intrinsic resistance to mTOR inhibitors. In both EpS cell lines, RAD001-induced AKT phosphorylation was dependent on c-MET signaling. INC280 inhibited phosphorylation of c-MET and its downstream molecules, and decreased RAD001-induced phosphorylation of both AKT and ERK in EpS. Compared with a single agent or control, the combination of RAD001 and INC280 exerted superior antitumor effects on the growth of EpS cell lines in vitro and in vivo . Conclusions Targeting of mTOR and c-MET signaling pathways significantly abrogates the growth of EpS in preclinical models and may be a promising therapeutic approach for patients with EpS.

Osteosarcoma is the most common malignant bone tumor in adolescence and childhood. Metastatic osteosarcoma has a poor prognosis with an overall 5‐year survival rate of approximately 20%. TAS‐115 is a novel multiple receptor tyrosine kinase inhibitor that is currently undergoing clinical trials. Using the mouse highly lung‐metastatic osteosarcoma cell line, LM8, we showed that TAS‐115 suppressed the growth of subcutaneous grafted tumor and lung metastasis of osteosarcoma at least partially through the inhibition of platelet‐derived growth factor receptor alpha, AXL, and Fms‐like tyrosine kinase 3 phosphorylation. We also show that these signaling pathways are activated in various human osteosarcoma cell lines and are involved in proliferation. Our results suggest that TAS‐115 may have potential for development into a novel treatment for metastatic osteosarcoma. TAS‐115 suppressed the growth of subcutaneous grafted tumor and lung metastasis of a mouse spontaneous highly metastatic osteosarcoma (OS) cell line, LM8. TAS‐115 exerts antitumor effects against OS cell lines partially via the inhibition of PDGFRα, AXL, and FLT‐3 signaling. TAS‐115 may be a potential novel therapeutic agent for patients with metastatic OS.

Clear cell sarcoma is an aggressive soft tissue sarcoma and highly resistant to conventional chemotherapy and radiation therapy. This devastating disease is defined by EWSR1‐ATF1 fusion gene resulting from chromosomal translocation t(12;22)(q13;q12) and characterized by melanocytic differentiation. A marine‐derived antineoplastic agent, trabectedin, inhibits the growth of myxoid liposarcoma and Ewing sarcoma by causing adipogenic differentiation and neural differentiation, respectively. In this study, we examined the antitumor effects and mechanism of action of trabectedin on human clear cell sarcoma cell lines. We showed that trabectedin decreased the cell proliferation of five clear cell sarcoma cell lines in a dose‐dependent manner in vitro and reduced tumor growth of two mouse xenograft models. Flow cytometry and immunoblot analyses in vitro and immunohistochemical analysis in vivo revealed that trabectedin‐induced G2/M cell cycle arrest and apoptosis. Furthermore, trabectedin increased the expression of melanocytic differentiation markers along with downregulation of ERK activity in vitro and the rate of melanin‐positive cells in vivo. These results suggest that trabectedin has potent antitumor activity against clear cell sarcoma cells by inducing cell cycle arrest, apoptosis, and, in part, by promoting melanocytic differentiation through inactivation of ERK signaling. Our present study indicates that trabectedin is a promising differentiation‐inducing agent for clear cell sarcoma. Clear cell sarcoma is an aggressive soft‐tissue sarcoma and highly resistant to conventional chemotherapy and radiation therapy. Our present study suggests that trabectedin has potent antitumor activity against clear cell sarcoma cells by inducing cell cycle arrest, apoptosis, and, in part, by promoting melanocytic differentiation.