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Naka N.,Japan National Cardiovascular Center Research Institute | Takenaka S.,Japan National Cardiovascular Center Research Institute | Takenaka S.,Osaka University | Araki N.,Japan National Cardiovascular Center Research Institute | And 10 more authors.
Stem Cells | Year: 2010

Synovial sarcoma (SS) is a malignant soft tissue tumor characterized by its unique t(X;18)(p11;q11) chromosomal translocation leading to the formation of the SS18-SSX fusion gene. The resulting fusion protein product is considered to play as an aberrant transcription factor and transform target cells by perturbing their gene expression program. However, the cellular origin of SS is highly debated. We herein established two novel human SS cell lines, named Yamato-SS and Aska-SS, and investigated their biological properties. We found the self-renewal ability of these cells to generate sarcospheres, to form tumors in serial xenotransplantation and reconstitute the tumor phenotypes without fractionation by any surface markers. Both SS cells as well as clinical tissue specimens from 15 patients expressed the marker genes-associated stem cell identity, Oct3/4, Nanog, and Sox2. We also found that both SS cells displayed limited differentiation potentials for mesenchymal lineages into osteocytes and chondrocytes albeit with the expression of early mesenchymal and hematopoietic lineage genes. Upon SS18-SSX silencing with sequence-specific siRNAs, these SS cells exhibited morphological transition from spherical growth in suspension to adherent growth in monolayer, additional expression of later mesenchymal and hematopoietic lineage genes, and broader differentiation potentials into osteocytes, chondrocytes, adipocytes, and macrophages in appropriate differentiation cocktails. Collectively, these data suggest that a human multipotent mesenchymal stem cell can serve as a cell of origin for SS and SS is a stem cell malignancy resulting from dysregulation of self-renewal and differentiation capacities driven by SS18-SSX fusion protein. © AlphaMed Press. Source


DiResta G.R.,New York University | Kakunaga S.,Kinki Block Comprehensive Cancer Center | Li D.,Peking University | Healey J.H.,Sloan Kettering Cancer Center
Frontiers in Oncology | Year: 2013

Background/Purpose: The effects of chemical and physical interactions in the microenvironment of solid tumors have not been fully elucidated. We hypothesized that acidosis, hypoxia, and elevated interstitial fluid pressure (eIFP) have additive effects on tumor cell biology and lead to more aggressive behavior during tumor progression. We investigated this phenomenon using three human osteosarcoma (OS) cell lines and a novel in vitro cell culture apparatus. Materials and Methods: U2OS, SaOS, and MG63 cell lines were cultured in media adjusted to various pH levels, oxygen tension (hypoxia 2% O2, normoxia 20% O2), and hydrostatic gage pressure (0 or 50 mmHg). Growth rate, apoptosis, cell cycle parameters, and expression of mRNA for proteins associated with invasiveness and tumor microenvironment (CA IX, VEGF-A, HIF-1A, MMP-9, and TIMP-2) were analyzed. Levels of CA IX, HIF-1a, and MMP-9 were measured using immunofluorescence. The effect of pH on invasiveness was evaluated in a Matrigel chamber assay. Results: Within the acidic-hypoxic-pressurized conditions that simulate the microenvironment at a tumor's center, invasive genes were upregulated, but the cell cycle was downregulated. The combined influence of acidosis, hypoxia, and IFP promoted invasiveness and angiogenesis to a greater extent than did pH, pO2, or eIFP individually. Significant cell death after brief exposure to acidic conditions occurred in each cell line during acclimation to acidic media, while prolonged exposure to acidic media resulted in reduced cell death. Furthermore, 48-h exposure to acidic conditions promoted tumor invasiveness in the Matrigel assay. Conclusion: Our findings demonstrate that tumor microenvironmental parameters - particularly pH, pO2, and eIFP - additively influence tumor proliferation, invasion, metabolism, and viability to enhance cell survival and must be controlled in OS research. © 2013 Matsubara, DiResta, Kakunaga, Li and Healey. Source


Takenaka S.,Japan National Cardiovascular Center Research Institute | Takenaka S.,Osaka University | Naka N.,Japan National Cardiovascular Center Research Institute | Araki N.,Japan National Cardiovascular Center Research Institute | And 5 more authors.
International Journal of Oncology | Year: 2010

Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by a unique t(X;18) translocation resulting in expression of SS18-SSX fusion protein. In order to investigate the biological function of this fusion protein and to develop a novel therapeutic option, we examined downregulation of SS18-SSX1 expression by small interfering RNA targeting SS18-SSX1 in three human SS cell lines. Microarray analysis comparing SS18-SSX1-silenced cells with control cells in three SS cell lines showed that SS18-SSX1 mainly affected the focal adhesion pathway. In accord with the array data, silencing of SS18-SSX1 enhances adhesion to the extracellular matrix through the induction of expression of myosin light-chain kinase. Furthermore, the silencing of SS18-SSX1 inhibits anchorage-independent growth in vitro and systemic delivery of siRNA against SS18-SSX1 using a nanoparticle system inhibited tumor growth in a nude mouse xenograft model. Our results demonstrate that siRNA targeting of SS18-SSX1 has therapeutic potential for the treatment of SS. Source


Yasui H.,Osaka University | Naka N.,Osaka University | Naka N.,Japan National Cardiovascular Center Research Institute | Imura Y.,Osaka University | And 9 more authors.
Cancer Letters | Year: 2014

We examined efficacy of the mTOR inhibitor RAD001 to seek novel therapies for synovial sarcoma (SS). Although RAD001 had significant anti-tumor effects, its sensitivity differed among cell lines. Phospho-receptor tyrosine kinase (RTK) array analyses revealed c-MET phosphorylation in highly mTOR inhibitor-sensitive cells and PDGFRα (which induces intrinsic resistance to mTOR inhibitor) activation in less sensitive cells. Combined treatment with RAD001 and the PDGFR inhibitor pazopanib showed anti-tumor effects in xenograft models with less sensitive cells. Thus, evaluating activated RTKs in clinical samples may predict sensitivity to mTOR inhibitors, raising the possibility of a tailored therapy for SS. © 2014 Elsevier Ireland Ltd. Source


Matsumine A.,Mie University | Ueda T.,Kinki Block Comprehensive Cancer Center | Sugita T.,National Hospital Organization Kure Medical Center and Chugoku Cancer Center | Yazawa Y.,International University of Japan | And 7 more authors.
Journal of Surgical Oncology | Year: 2011

Background and Objectives: The KYOCERA Physio Hinge Total Knee System Type III (PHKIII) was developed to reconstruct bony defects of the distal femur. The PHKIII is originative in that the metallic parts are fully made of titanium alloy, and this prosthesis has a unique semi-rotating hinge joint and was designed especially for people with the Asian physical body-type. The clinical outcomes of the PHKIII after the resection of musculoskeletal tumors of the distal femur were evaluated. Methods: There were 41 males and 28 females with a median age of 48-years. The median duration of follow-up was 57 months. Results: Eleven early complications and 37 late complications were observed, including 10 recurrences, 7 deep infections, 7 aseptic loosenings, 4 stem breakages, 4 displacements of shaft cap, and one wear of rotation sleeve. Twenty four prosthesis (35%) required a secondary operation because of complications. The five-year overall prosthetic survival rates, -prosthetic survival rate without aseptic loosening, and -limbs preservation rate were 85%, 90%, and 86%, respectively. The mean functional score according to the classification system of the Musculoskeletal Tumor Society was 20.5 points (68%). Conclusions: Although continuous follow-up is required, reconstructions using PHKIII are considered to achieve more acceptable functional results. © 2010 Wiley-Liss, Inc. Source

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