EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins.
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.
Potikyan
Gary
G
Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024, USA.
Savene
Rupert O V
RO
Gaulden
Julie M
JM
France
Kelly A
KA
Zhou
Zhichao
Z
Kleinerman
Eugenie S
ES
Lessnick
Stephen L
SL
Denny
Christopher T
CT
D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology; D019699:Thrombospondins / Q000096:biosynthesis*; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*
C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D019699:Thrombospondins; D014157:Transcription Factors