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HIF-1 and tumor progression: pathophysiology and therapeutics Solid tumors measuring less than 1 to 2 cubic millimeters are typically not highly vascularized. Beyond the critical volume of 2 cubic millimeters, oxygen and nutrients have difficulty diffusing to the cells in the center of the tumor. This promotes a state of cellular hypoxia. To preserve the function of critical organs, human and other eukaryotic cells have developed the ability to respond to hypoxia. The concept of oxygen regulated peptides (ORPs) was first introduced in the mid-1980's when studies demonstrated that hypoxia induced a series of cell survival proteins that were distinct from the heat shock protein and glucose regulated protein families. In 1991, ORPs were reported to be induced in ischemic endothelial cells and myocytes. This was proposed to protect blood vessel integrity during anoxia. The response to anoxia was further determined in human cells and it was reported that aortic, pulmonary artery, and microvascular endothelial cells all over-expressed ORPs under low oxygen tension. Targeting ORPs offers an attractive approach to the treatment of ischemic diseases such as stroke, myocardial infarction and peripheral arterial obstructive disease. However tumors have also highjacked this cellular response, in particular through the induced expression of proteins such as ORP150 (see our dossier published last year entitled "Oxygen regulated proteins as novel therapies for atherosclerosis, stroke, diabetes and cancer") and hypoxia-inducible factor 1 (HIF-1). HIF-1 controls oxygen delivery (via angiogenesis) and metabolic adaptation to hypoxia (via glycolysis). HIF-1 consists of a constitutively expressed HIF-1beta subunit and an oxygen- and growth-factor-regulated HIF-1alpha subunit. In xenografts, tumor growth and angiogenesis are correlated with HIF-1 expression. In human cancers, HIF-1alpha is overexpressed as a result of intratumoral hypoxia and genetic alterations affecting key oncogenes and tumor suppressor genes. HIF-1alpha overexpression in biopsies of brain, breast, cervical, esophageal, oropharyngeal and ovarian cancers is correlated with treatment failure and mortality. Increased HIF-1 activity promotes tumor progression, and inhibition of HIF-1 could represent a novel approach to cancer therapy. Link to journal abstract:
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