Downregulation of angiogenic factors in Ewing tumor xenografts by the combination of human interferon-alpha or interferon-beta with ifosfamide.
Ewing sarcoma is the second most common bone tumor in childhood. Despite aggressive chemotherapy and radiotherapy, the prognosis of metastatic disease remains poor. In a nude mouse model of Ewing tumor xenografts, we recently showed that human type I interferons (IFNs) inhibit the growth of established xenografts. Combined therapy with human IFNs and ifosfamide (IFO), an alkylating agent widely used in high-dose chemotherapy of Ewing tumors, results in a strong synergistic antitumor effect. We have investigated the effect of IFNs/IFO treatment on the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP-9), and urokinase plasminogen activator receptor (uPAR), three key mediators of tumor growth and angiogenesis, in tumor xenografts generated either from a primary tumor (EW7) or from a metastatic tumor (COH). COH tumors expressed 5-fold higher levels of VEGF than EW7 tumors. IFNs/IFO treatment reduced by >70% the amount of VEGF in COH and EW7 tumors. We did not detect constitutive MMP-9 activity in EW7 tumors. In contrast, the metastasis-derived COH tumor expressed very high levels of active MMP-9. Although the total amount of MMP-9 remained unchanged, active MMP-9 was reduced by up to 75% in IFNs/IFO-treated COH tumors. IFNs/IFO treatment triggered in both COH and EW7 tumors the downregulation of uPAR expression, a molecule involved in vascularization and endothelial cell migration. Our results partly explain the mechanism of tumor growth inhibition by IFNs/IFO therapy and provide a rational foundation for the development of a new therapeutic approach to Ewing tumors resistant to conventional chemotherapy.
Sancéau
Josiane
J
Institut National de la Santé et de la Recherche Médicale U365, Institut Curie, Section Recherche 26, rue d'Ulm, 75 248, Paris 05, Cedex, France. jwietzer@curie.fr.
Wietzerbin
Juana
J
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000494:pharmacology*; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D016899:Interferon-beta / Q000008:administration & dosage / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D017931:DNA Primers; D016898:Interferon-alpha; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9; D007069:Ifosfamide