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Thiel U.,Childrens Cancer Research Center | Pirson S.,Childrens Cancer Research Center | Muller-Spahn C.,Childrens Cancer Research Center | Conrad H.,III. Medizinische Klinik and Poliklinik Hematology Oncology | And 4 more authors.
British Journal of Cancer | Year: 2011

Background:The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8 + T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods:Following repetitive CHM1 319 (VIMPCSWWV) and EZH2 666 (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201 dendritic cells (DC), allo-restricted HLA-A 0201 CD8 +T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results:Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201 ET lines expressing the antigen while HLA-A 0201- ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2 / γ C / mice. Within this context, we identified the CHM1 319 peptide as a new candidate target antigen for ET immunotherapy.Conclusion:These results clearly identify the ET-derived antigens, EZH2 666 and CHM1 319, as suitable targets for protective allo-restricted human CD8 T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation. © 2011 Cancer Research UK All rights reserved.

Frietsch J.J.,University of Würzburg | Grunewald T.G.P.,Childrens Cancer Research Center | Jasper S.,University of Würzburg | Kammerer U.,University of Würzburg | And 4 more authors.
British Journal of Cancer | Year: 2010

Background:LIM and SH3 protein 1 (LASP-1) is a nucleo-cytoplasmatic signalling protein involved in cell proliferation and migration and is upregulated in breast cancer in vitro studies have shown that LASP-1 might be regulated by prostate-derived ETS factor (PDEF), p53 and/or LASP1 gene amplification. This current study analysed the prognostic significance of LASP-1 on overall survival (OS) in 177 breast cancer patients and addressed the suggested mechanisms of LASP-1-regulation.Methods:Nucleo-cytoplasmatic LASP-1-positivity of breast carcinoma samples was correlated with long-term survival, clinicopathological parameters, Ki67-positivity and PDEF expression. Rate of LASP1 amplification was determined in micro-dissected primary breast cancer cells using quantitative RT-PCR. Cell-phase dependency of nuclear LASP-1-localisation was studied in synchronised cells. In addition, LASP-1, PDEF and p53 expression was compared in cell lines of different tumour entities to define principles for LASP-1-regulation.Results:We showed that LASP-1 overexpression is not due to LASP1 gene amplification. Moreover, no correlation between p53-mutations or PDEF-expression and LASP-1-status was observed. However, nuclear LASP-1-localisation in breast carcinomas is increased during proliferation with peak in G2/M-phase and correlated significantly with Ki67-positivity and poor OS.Conclusion:Our results provide evidence that nuclear LASP-1-positivity may serve as a negative prognostic indicator for long-term survival of breast cancer patients. © 2010 Cancer Research UK All rights reserved.

Hauer K.,Childrens Cancer Research Center | Calzada-Wack J.,Helmholtz Center for Environmental Research | Steiger K.,Helmholtz Center for Environmental Research | Grunewald T.G.P.,Childrens Cancer Research Center | And 8 more authors.
Cancer Research | Year: 2013

Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFb1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1a, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells. © 2012 AACR.

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