DNA Microarrays Reveal Relationship of Ewing Family Tumors to Both Endothelial and Fetal Neural Crest-Derived Cells and Define Novel Targets

Staege, Martin S.; Hutter, Christoph; Neumann, Ingo; Foja, Sabine; Hattenhorst, Uwe; Hansen, Gesine; Afar, Danny; Burdach, Stefan

doi:10.1158/0008-5472.can-03-4059

Cited by 194 publications

(221 citation statements)

References 43 publications

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“…EWS/FLI1 encodes an oncogenic transcription factor that determines the complex and highly malignant phenotype of Ewing tumors (2). Hence, the detailed functional characterization of the EWS/FLI1-induced transcriptome may be key to understand the underlying mechanisms of the disease and ultimately to halt its progression (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we identified a specific expression signature of approximately 40 genes that are highly upregulated in Ewing tumors compared with benign tissues (3). Part of this signature is the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound protein possibly contributing to transmembrane electron transfer (5,6).…”

Section: Introductionmentioning

confidence: 99%

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STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Grünewald

Diebold

Espósito

et al. 2012

Molecular Cancer Research

115

132

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Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1. Mol Cancer Res; 10(1); 52-65. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Grünewald

Diebold

Espósito

et al. 2012

Molecular Cancer Research

115

132

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“…30,31 MYCN expression has not been reported in Ewing sarcoma/primitive neuroectodermal tumor. 32,33 In order to investigate the potential diagnostic usefulness of these findings, the current study examined the expression pattern of MYCN in a series of 12 synovial sarcomas and 29 other pediatric sarcomas by RT-PCR. In addition, the status of MYCN gene amplification and expression of downstream targets of MYCN was assessed in synovial sarcoma.…”

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confidence: 99%

Expression of MYCN in pediatric synovial sarcoma

et al. 2007

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Synovial sarcoma accounts for between 6 and 10% of childhood sarcomas and histological diagnosis can be challenging, even for experienced pathologists. Several other tumors enter the differential diagnosis, including malignant peripheral nerve sheath tumor, Ewing sarcoma/primitive neuroectodermal tumor and undifferentiated sarcoma. Several recent reports utilizing expression array techniques have documented expression of the MYCN oncogene in synovial sarcoma. In order to more fully investigate this finding, a series of 12 synovial sarcomas and 29 other sarcomas (four malignant peripheral nerve sheath tumors, 15 Ewing sarcoma/primitive neuroectodermal tumors, 10 undifferentiated sarcomas) were examined for MYCN expression and gene amplification. By RT-PCR, nine of 12 synovial sarcomas (75%) expressed MYCN. Five synovial sarcomas (42%) expressed MYCN at high levels. Of the other sarcomas, one malignant peripheral nerve sheath tumor (25%) and five Ewing sarcoma/primitive neuroectodermal tumors (33%) expressed MYCN at low levels, and all other cases were negative for MYCN. None of the synovial sarcomas had genomic amplification, suggesting that high MYCN expression levels resulted from epigenetic phenomena. Examination of selected downstream targets of MYCN in synovial sarcoma revealed expression of MCM7 (minichromosome maintenance protein 7) in all synovial sarcomas, and expression of nestin (n ¼ 10; 83%), ID2 (inhibitor of DNA binding protein 2) (n ¼ 6; 50%) and MRP1 (multidrug resistance protein 1) (n ¼ 1; 8%) in a subset of synovial sarcomas. Expression of downstream targets did not correlate with expression of MYCN. Neither MYCN nor expression of downstream targets significantly correlated with metastases at presentation, progression-free survival or overall survival in this small series. In summary, high levels of MYCN expression was useful for distinguishing synovial sarcoma from other childhood-spindled cell sarcomas with specificity and sensitivity of 100 and 42%, respectively, in this series. The clinical and biological significance of this finding deserves further study.

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“…18 In samples obtained from refractory tumor before adoptive transfer, CHM1 was overexpressed compared to healthy body tissue in patients #2 and #3, and more moderately expressed in patient #1 (Fig. 1A).…”

Section: Expression Of Target Genesmentioning

confidence: 93%

Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells

et al. 2017

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Background: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A Ã 02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8 C ) T cells against ES. Patients and Methods: Three refractory HLA-A2 C ES patients were treated with HLA-A Ã 02:01/peptidespecific allorepertoire-derived (i.e., allorestricted) CD8 C T cells. Patient #1 received up to 4.8 £ 10 5 /kg body weight HLA-A Ã 02:01 ¡ allorestricted donor-derived wild-type CD8 C T cells. Patient #2 received up to 8.2 £ 10 6 /kg HLA-A Ã 02:01 ¡ donor-derived and patient #3 up to 6 £ 10 6 /kg autologous allorestricted TCR transgenic CD8 C T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1 319 ). Results: HLA-A Ã 02:01/CHM1 319 -specific allorestricted CD8 C T cells showed specific in vitro lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1 319 TCR transgenic T cells could be tracked in his BM for weeks. Conclusions: CHM1 319 -TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A Ã 02:01/antigen-specific allorestricted T cells proliferate in vivo without causing GvHD.

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DNA Microarrays Reveal Relationship of Ewing Family Tumors to Both Endothelial and Fetal Neural Crest-Derived Cells and Define Novel Targets

Cited by 194 publications

References 43 publications

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Expression of MYCN in pediatric synovial sarcoma

Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells

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