The family of a disintegrin and metalloproteinase (ADAM) proteins has been implicated in tumor initiation and progression. ADAM17/TNFa converting enzyme has been initially recognized to release TNFa as well as its receptors (TNFR) from the membrane. ADAM17, TNFa and TNFR have been found upregulated in cancer patients although the underlying mechanisms remain largely unknown. Since hypoxia is a hallmark of cancer which can lead to severe stress conditions accumulating in endoplasmatic reticulum (ER) stress and the unfolded protein response (UPR), we investigated the role of these stress conditions in the regulation of ADAM17. Severe hypoxia induced ADAM17 expression and activity. Although HIF1a was important to maintain basal ADAM17 mRNA levels during moderate hypoxia, it was not sufficient to induce ADAM17 levels under severe hypoxia. Instead, we found that ADAM17 induction by severe hypoxia can be mimicked by ER-stressors such as thapsigargin and occurs as a consequence of the activation of the PERK/eIF2a/ATF4 and ATF6 arms of UPR in several tumor cell lines. ADAM17 expression was also increased in xenografts displaying ER-stress due to treatment with the VEGF inhibitory antibody Bevacizumab. Additionally, severe hypoxia and ER-stress activated ADAM17 and ectodomain shedding of TNFR1 by a mechanism involving ERK and p38 MAP kinase. Collectively, these results show that ADAM17 is a novel UPR-regulated gene in response to severe hypoxia and ER-stress, which is actively involved in the release of TNFR1 under these conditions. These data provide a novel link between severe hypoxic stress conditions and inflammation in the tumor environment.