Interferon-alpha as angiogenesis inhibitor: learning from tumor models

Interferon-alpha (IFN-alpha), a cytokine with marked therapeutic activity in transplantable tumor models, has been identified as powerful angiogenesis inhibitor. The effects of IFN-alpha on the vasculature have been mainly attributed to inhibition of basic fibroblast growth factor production by tumor cells or downregulation of IL-8 and vascular endothelial growth factor gene expression. Moreover, IFN-alpha has direct effects on endothelial cells (EC), including impairment of their proliferation and migration. The gene expression profile induced by IFN-alpha in EC has recently been defined, and it was found that several genes encoding negative regulators of angiogenesis are upmodulated, thus providing a potential amplification mechanism for this biological activity. The anti-angiogenic effects of IFN-alpha appear to be associated with increased hypoxia and ischemic necrosis in subcutaneous xenograft models, whereas in transgenic mouse models, IFN-alpha may simultaneously interfere with both blood vessels and tumor cell proliferation, leading to regression of tumors without necrosis. The consequences of IFN-alpha therapy on the invasive and metastatic behavior of tumor cells are currently unknown. Finally, as effective anti-angiogenic therapy with IFN-alpha demands sustained localized production of this cytokine, innovative strategies of targeted delivery of the IFN-alpha gene into tumors are discussed.