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Fig. 2 | Journal of Hematology & Oncology

Fig. 2

From: Cancer and COVID-19: unravelling the immunological interplay with a review of promising therapies against severe SARS-CoV-2 for cancer patients

Fig. 2

SARS-CoV-2 & Cancer-induced Hypoxia. SARS-CoV-2 and cancer induce hypoxia resulting in cellular necrosis and upregulation of the TLR4 pathway and HIF-1α. This results in increased secretion of IL-1β that stimulates NF-κB to cause mitochondrial dysfunction, secretion of reactive oxygen species and subsequent inflammation. IL-1β stimulates IL-1RI to cause alveolar macrophages pyroptosis to cause inflammatory damage. Hypoxia, IL-1β, and HIF-1α stimulate cyclooxygenase-2 (COX-2) which catalyzes the breakdown of arachidic acid into prostaglandin H2 (PGH2). Further breakdown with COX-1 and 2 results in the production of prostacyclin, prostaglandin, and thromboxane. Hypoxic metabolic derangements result in the accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER) resulting in activation of the unfolded protein response (UPR). This activates inositol-requiring enzyme 1 (IRE-1), which catalyzes the transcription of X-box binding protein 1 (XBP-1) and results in secretion of IL-1β and IL-6, which turn on downstream pro-inflammatory pathways. Additionally, hypoxia activates protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK kinase) within the ER that stimulates activating transcription factor 4 (ATF4)-dependent transcriptional activation that results in secretion of IL-6 to promote inflammation. Additionally, HIF-1α, ATF4, and XBP-1 stimulate the release of vascular endothelial growth factor (VEGF). VEGF contributes to pulmonary inflammation and promotes vascular permeability resulting in pulmonary edema, which further exacerbates tissue hypoxia. The image of SARS-CoV-2 was derived from the Centers for Disease Control and Prevention (CDC) website: https://phil.cdc.gov/Details.aspx?pid=23312

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