EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins

Gary Potikyan; Rupert O.V. Savene; Julie M. Gaulden; Kelly A. France; Zhichao Zhou; Eugenie S. Kleinerman; Stephen L. Lessnick; Christopher T. Denny

doi:10.1158/0008-5472.CAN-06-4140

EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins

Gary Potikyan, Rupert O.V. Savene, Julie M. Gaulden, Kelly A. France, Zhichao Zhou, Eugenie S. Kleinerman, Stephen L. Lessnick, Christopher T. Denny

Pediatrics

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor-derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.

Original language	English (US)
Pages (from-to)	6675-6684
Number of pages	10
Journal	Cancer Research
Volume	67
Issue number	14
DOIs	https://doi.org/10.1158/0008-5472.CAN-06-4140
State	Published - Jul 15 2007

ASJC Scopus subject areas

Oncology
Cancer Research

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title = "EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins",

abstract = "Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor-derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.",

author = "Gary Potikyan and Savene, {Rupert O.V.} and Gaulden, {Julie M.} and France, {Kelly A.} and Zhichao Zhou and Kleinerman, {Eugenie S.} and Lessnick, {Stephen L.} and Denny, {Christopher T.}",

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AU - Potikyan, Gary

AU - Savene, Rupert O.V.

AU - Gaulden, Julie M.

AU - France, Kelly A.

AU - Zhou, Zhichao

AU - Kleinerman, Eugenie S.

AU - Lessnick, Stephen L.

AU - Denny, Christopher T.

PY - 2007/7/15

Y1 - 2007/7/15

N2 - Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor-derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.

AB - Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor-derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.

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EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins

Abstract

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