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Sebastian Michels,
Marcel Trautmann,
Elisabeth Sievers,
Dagmar Kindler,
Sebastian Huss,
Marcus Renner,
Nicolaus Friedrichs,
Jutta Kirfel,
Susanne Steiner,
Elmar Endl, [......],
Roland Penzel,
Olle Larsson,
Akira Kawai, Shinya Tanaka,
Hiroshi Sonobe,
Peter Schirmacher,
Gunhild Mechtersheimer,
Eva Wardelmann,
Reinhard Büttner,
Wolfgang Hartmann
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ABSTRACT: Synovial sarcoma is a soft-tissue malignancy characterized by a reciprocal t(X;18) translocation encoding a chimeric transcriptional modifier. Several receptor tyrosine kinases have been found activated in synovial sarcoma; however, no convincing therapeutic concept has emerged from these findings. On the basis of the results of phosphokinase screening arrays, we here investigate the functional and therapeutic relevance of the SRC kinase in synovial sarcoma. Immunohistochemistry of phosphorylated SRC and its regulators CSK and PTP1B (PTPN1) was conducted in 30 synovial sarcomas. Functional aspects of SRC, including dependence of SRC activation on the SS18/SSX fusion proteins, were analyzed in vitro. Eventually, synovial sarcoma xenografts were treated with the SRC inhibitor dasatinib in vivo. Activated phospho (p)-(Tyr416)-SRC was detected in the majority of tumors; dysregulation of CSK or PTP1B was excluded as the reason for the activation of the kinase. Expression of the SS18/SSX fusion proteins in T-REx-293 cells was associated with increased p-(Tyr416)-SRC levels, linked with an induction of the insulin-like growth factor pathway. Treatment of synovial sarcoma cells with dasatinib led to apoptosis and inhibition of cellular proliferation, associated with reduced phosphorylation of FAK (PTK2), STAT3, IGF-IR, and AKT. Concurrent exposure of cells to dasatinib and chemotherapeutic agents resulted in additive effects. Cellular migration and invasion were dependent on signals transmitted by SRC involving regulation of the Rho GTPases Rac and RhoA. Treatment of nude mice with SYO-1 xenografts with dasatinib significantly inhibited tumor growth in vivo. In summary, SRC is of crucial biologic importance and represents a promising therapeutic target in synovial sarcoma. Cancer Res; 73(8); 1-11. ©2013 AACR.
Cancer Research 04/2013; · 7.86 Impact Factor
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Hans-Ulrich Schildhaus,
Raffael Riegel,
Wolfgang Hartmann,
Susanne Steiner,
Eva Wardelmann,
Sabine Merkelbach-Bruse, Shinya Tanaka,
Hiroshi Sonobe,
Roland Schüle,
Reinhard Buettner,
Jutta Kirfel
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ABSTRACT: Epigenetic changes including histone methylation, histone acetylation, and DNA methylation are thought to play important roles in the onset and progression of cancer in numerous tumor types. Recent evidence shows that dysregulated epigenetic modifications are as significant as genetic mutations and can act as oncogenic driver lesions causing autonomous growth of cancer cells. Here, we investigated the role of lysine-specific demethylase 1 in mesenchymal tumors. Lysine-specific demethylase 1 is the first discovered histone lysine demethylase and can demethylate both H3K4me2/1 and H3K9me2/1. By analyzing a total of 468 tumors, we describe for the first time high lysine-specific demethylase 1 expression in several highly malignant sarcomas, including synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors and malignant peripheral nerve sheath tumors. Among the intermediate tumors only solitary fibrous tumors were found to be highly lysine-specific demethylase 1 positive, whereas lysine-specific demethylase 1 expression was low or absent in benign tumors. Lysine-specific demethylase 1 inhibition with small molecule inhibitors resulted in growth inhibition of synovial sarcoma cells in vitro and an increase in global H3K4me2 methylation. Sarcomas continue to remain a clinical challenge and therefore the identification of both diagnostic markers and novel drug targets for the development of new therapeutic options are needed. Our results suggest that dysregulation of lysine-specific demethylase 1 is associated with highly malignant sarcomas proposing them as molecular tumor markers as well as targets for the treatment of these tumor types.
Human pathology 04/2011; 42(11):1667-75. · 3.03 Impact Factor
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Nicolaus Friedrichs,
Marcel Trautmann,
Elmar Endl,
Elisabeth Sievers,
Dagmar Kindler,
Peter Wurst,
Jacqueline Czerwitzki,
Susanne Steiner,
Marcus Renner,
Roland Penzel,
Arend Koch,
Olle Larsson, Shinya Tanaka,
Akira Kawai,
Peter Schirmacher,
Gunhild Mechtersheimer,
Eva Wardelmann,
Reinhard Buettner,
Wolfgang Hartmann
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ABSTRACT: Synovial sarcomas account for 5-10% of all malignant soft tissue tumors. They have been shown to express different membranous growth factor receptors, many of them signaling via intracellular kinase cascades. In our study, the functional role of PI3K/AKT signals in synovial sarcoma is analyzed with regard to tumor biology and therapeutic applicability. Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT, its targets p-(Ser9)-GSK-3β and p-(Ser2448)-mTOR and the cell cycle regulators Cyclin D1 and p27(KIP1) were performed in 36 synovial sarcomas. The PIK3CA gene was screened for mutations. In vitro, four synovial sarcoma cell lines were treated with the PI3K inhibitor LY294002. Phosphorylation of AKT, GSK-3β and mTOR was assessed, and cellular proliferation and apoptosis were analyzed to functionally characterize the effects of PI3K inhibition. Finally, coincubations of LY294002 with cytotoxic drugs were performed. Most tumors showed significant expression levels of p-AKT, p-GSK-3β and p-mTOR, indicating activation of the PI3K/AKT signaling cascade in synovial sarcomas; Cyclin D1 and p27(KIP1) were differentially expressed. Mutations in the PIK3CA gene could be excluded. In vitro, PI3K inhibition diminished synovial sarcoma cell growth accompanied by reduced phosphorylation of AKT, GSK-3β and mTOR. Mechanistically, PI3K pathway inhibition lead to enhanced apoptosis and decreased cellular proliferation linked to reduced Cyclin D1 and increased p27(KIP1) levels. Simultaneous treatment of synovial sarcoma cell lines with LY294002 and cytotoxic drugs resulted in additive effects. In summary, PI3K signaling plays an essential role in growth control of synovial sarcomas and might be successfully targeted in multimodal therapeutic strategies.
International Journal of Cancer 12/2010; 129(7):1564-75. · 5.44 Impact Factor
