In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1-dependent signaling pathways and to complex signaling events known as the unfolded protein response. Here, we show that the activation of the endoplasmic reticulum stress sensor IRE1 is a common determinant linking hypoxia-and hypoglycemia-dependent responses to the up

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The liver is a major site of metastases for some of the most common human malignancies, carcinomas of the gastrointestinal tract in particular. Liver metastases are frequently inoperable and are associated with poor prognosis. 1 The metastatic cascade involves a sequence of steps that can lead to tumor cell arrest in the vascular bed of an invaded organ such as the liver and subsequently to tumor extravasation into the extravascular space.2 These events are regulated by, and in turn, can induce host proinflammatory responses that involve tumor-and host-derived chemokines and cytokines. A key mediator of the inflammatory response is tumor necrosis factor (TNF)-␣. This cytokine can play a dual role in tumor progression and metastasis. On one hand it can inhibit tumor growth through its cytocidal and proapoptotic activities but on the other, it can promote tumor progression through different mechanisms such as the induction of vascular endothelial adhesion receptors and the promotion of growth, invasion, and metastasis. The ultimate effect of TNF-␣ may depend on its concentrations, on tumor cell susceptibility, and on the stage of the disease. 3,4