Erythropoietin Blockade Inhibits the Induction of Tumor Angiogenesis and Progression

BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody) with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer

The "Abnormal" State : Identity, Norm/Exception and Japan

The term ‘abnormal’ has frequently been used to describe post-war Japan. Together with the idea that the country will, or should have to, ‘normalise’ its foreign and security policy, it has been reproduced in both academia and Japanese society. Why is Japan branded as ‘abnormal’, and from where does the desire to ‘normalise’ it come? Drawing on a relational concept of identity, and the distinction between norm and exception, this article argues that the ‘abnormality–normalisation nexus’ can be understood in terms of three identity-producing processes: (1) the process whereby the Japanese Self is socialised in US/‘Western’ norms, ultimately constructing it as an Other in the international system; (2) the process whereby the Japanese Self imagines itself as ‘legitimately exceptional’ (what is called ‘exceptionalisation’), but also ‘illegitimately abnormal’ — both of which are epitomised by Japan’s ‘pacifism’; and (3) the process whereby both the Self’s ‘negative abnormality’ and China/Asia are securitised in attempts to realise a more ‘normal’ (or super-normal) Japanese Self. How Japan is inter subjectively constructed on a scale between ‘normal’ and ‘abnormal’ enables and constrains action. Although Japan has not remilitarised nearly as much in the 2000s as is often claimed, these processes might very well forebode an exceptional decision to become ‘normal’ and therefore more significant steps towards remilitarisation