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Hypoxia is a universal feature of solid cancers caused by a mismatch between cellular oxygen supply and consumption. To meet the increased demand for oxygen, hypoxic cancer cells (CCs) induce a multifaceted process known as angiogenesis, wherein new vessels are formed by the sprouting of pre-existing ones. In addition to providing oxygen for growth and an exit route for dissemination, angiogenic vessels and factors are co-opted by CCs to enable the generation of an immunotolerant, hypoxic tumor microenvironment, leading to therapeutic failure and mortality. In this review, we discuss how hypoxia-inducible factors (HIFs), the mechanistic target of rapamycin (mTOR), and the unfolded protein response (UPR) control angiogenic factors serving both vascular and immunomodulatory functions in the tumor microenvironment. Possible therapeutic strategies, wherein targeting oxygen sensing might enhance anti-angiogenic and immunologically-mediated anti-cancer responses, are suggested. [ABSTRACT FROM AUTHOR]

Molecular oxygen (O 2 ) is a universal electron acceptor that enables ATP synthesis through mitochondrial respiration in all metazoans. Consequently, hypoxia (low O 2 ) has arisen as an organizing principle for cellular evolution, metabolism, and (patho)biology, eliciting a remarkable panoply of metabolic adaptations that trigger transcriptional, translational, post-translational, and epigenetic responses to determine cellular fitness. In this review we summarize current and emerging cell-autonomous molecular mechanisms that induce hypoxic metabolic reprogramming in health and disease. [ABSTRACT FROM AUTHOR]

Dissemination of breast cancer cells (BCCs) to distant sites (metastasis) is the ultimate cause of mortality in patients with breast cancer. Hypoxia (low O 2 ) is a microenvironmental hallmark of most solid cancers arising as a mismatch between cellular O 2 consumption and supply. Hypoxic selection of BCCs triggers molecular and cellular adaptations dependent upon hypoxia-inducible factors (HIFs), a family of evolutionarily conserved transcriptional activators that coordinate the expression of numerous genes controlling each step of the metastatic process. In this review, we summarize current advances in the understanding of HIF-driven molecular mechanisms that promote BCC metastatic dissemination and patient mortality. In addition, we discuss the clinical and therapeutic implications of HIF targeting in breast cancers. [ABSTRACT FROM AUTHOR]

Hypoxia (low O 2 ) is an essential microenvironmental driver of phenotypic diversity in human solid cancers. Hypoxic cancer cells hijack evolutionarily conserved, O 2 - sensitive pathways eliciting molecular adaptations that impact responses to radiotherapy, tumor recurrence and patient survival. In this review, we summarize the radiobiological, genetic, epigenetic and metabolic mechanisms orchestrating oncogenic responses to hypoxia. In addition, we outline emerging hypoxia- targeting strategies that hold promise for individualized cancer therapy in the context of radiotherapy and drug delivery. [ABSTRACT FROM AUTHOR]

Aims Hypoxia-inducible factor 1 (HIF-1) is a heterodimer composed of HIF-1α and HIF-1β subunits. HIF-1 is known to promote tissue vascularization by activating the transcription of genes encoding angiogenic factors, which bind to receptors on endothelial cells (ECs) and bone marrow-derived angiogenic cells (BMDACs). In this study, we analysed whether HIF-1 activity in the responding ECs and BMDACs is also required for cutaneous vascularization during burn wound healing. Methods and results We generated mice with floxed alleles at the Hif1a or Arnt locus encoding HIF-1α and HIF-1β, respectively. Expression of Cre recombinase was driven by the Tie2 gene promoter, which is expressed in ECs and bone marrow cells. Tie2Cre+ and Tie2Cre− mice were subjected to burn wounds of reproducible diameter and depth. Deficiency of HIF-1α or HIF-1β in Tie2-lineage cells resulted in delayed wound closure, reduced vascularization, decreased cutaneous blood flow, impaired BMDAC mobilization, and decreased BMDAC homing to burn wounds. Conclusion HIF-1 activity in Tie2-lineage cells is required for the mobilization and homing of BMDACs to cutaneous burn wounds and for the vascularization of burn wound tissue. [ABSTRACT FROM AUTHOR]

The vascular system delivers oxygen and nutrients to every cell in the vertebrate organism. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of hypoxic/ischaemic vascular responses, driving transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis, arteriogenesis, and the mobilization and homing of bone marrow-derived angiogenic cells. This review will focus on the pivotal role of HIF-1 in vascular homeostasis, the involvement of HIF-1 in vascular diseases, and recent advances in targeting HIF-1 for therapy in preclinical models. [ABSTRACT FROM PUBLISHER]

lschemia induces the production of angiogenic cytokines and the homing of bone-marrow-derived angiogenic cells (BMDACs), but these adaptive responses become impaired with aging because of reduced expression of hypoxia-inducible factor (HlF)-1α. In this study, we analyzed the effect of augmenting HIF-1α levels in ischemic limb by intramuscular injection of AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, and intravenous administration of BMDACs that were cultured in the presence of the prolyl-4-hydroxylase inhibitor dimethyloxalyiglycine (DMOG) to induce HIF-1 expression. The combined therapy increased perfusion. motor.function, and limb salvage in old mice subjected to femoral artery ligation. Homing of BMDACs to the ischemic limb was dramatically enhanced by intramuscular AdCA5 administration. DMOG treatment of BMDACs increased cell surface expression of β2 integrins. which mediated increased adherence of BMDACs to endothelial cells. The effect of DMOG was abolished by coadministration of the HIF-1 inhibitor digoxin or by preincubation with a 132 integrin-blocking antibody. Transduction of BMDACs with lentivirus LvCA5 induced effects similar to DMOG treatment. Thus, HIF-1α gene therapy increases homing of BMDACs to ischemic muscle, whereas HIF-1 induction in BMDAC5 enhances their adhesion to vascular endothelium, leading to synergistic effects of combined therapy on tissue perfusion. [ABSTRACT FROM AUTHOR]

Using a cell-based reporter gene assay, we screened a library of drugs in clinical use and identified the anthracycline chemotherapeutic agents doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. These drugs inhibited HIF-1 by blocking its binding to DNA. Daily administration of doxorubicin or daunorubicin potently inhibited the transcription of a HIF-1-dependent reporter gene as well as endogenous HIF-1 target genes encoding vascular endothelial growth factor, stromal-derived factor 1, and stem cell factor in tumor xenografts. CXCR4+/sca1+, VEGFR2+/CD34+, and VEGFR2+/ CD117+ bone-marrow derived cells were increased in the peripheral blood of SCID mice bearing prostate cancer xenografts but not in tumor-bearing mice treated for 5 days with doxorubicin or daunorubicin, which dramatically reduced tumor vascularization. These results provide a molecular basis for the antiangiogenic effect of anthracycline therapy and have important implications for refining the use of these drugs to treat human cancer more effectively. [ABSTRACT FROM AUTHOR]

HIF-1 is a heterodimeric transcription factor that mediates adaptive responses to hypoxia and plays critical roles in cancer progression. Using a cell-based screening assay we have identified acriflavine as a drug that binds directly to HIF-1α and HIF-2α and inhibits HIF-1 dimerization and transcriptional activity. Pretreatment of mice bearing prostate cancer xenografts with acriflavine prevented tumor growth and treatment of mice bearing established tumors resulted in growth arrest. Acriflavine treatment inhibited intratumoral expression of angiogenic cytokines. mobilization of angiogenic cells into peripheral blood, and tumor vascularization. These results provide proof of principle that small molecules can inhibit dimerization of HIF-1 and have potent inhibitory effects on tumor growth and vascularization. [ABSTRACT FROM AUTHOR]

A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1α protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1α bytransfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy. [ABSTRACT FROM AUTHOR]