Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we ...report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5'-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation.
Hypoxia inducible factors (HIFs) are α/β heterodimeric transcription factors that direct multiple cellular and systemic responses in response to changes in oxygen availability. The oxygen sensitive ...signal is generated by a series of iron and 2-oxoglutarate–dependent dioxygenases that catalyze post-translational hydroxylation of specific prolyl and asparaginyl residues in HIFα subunits and thereby promote their destruction and inactivation in the presence of oxygen. In hypoxia, these processes are suppressed allowing HIF to activate a massive transcriptional cascade. Elucidation of these pathways has opened several new fields of cardiovascular research. Here, we review the role of HIF hydroxylase pathways in cardiac development and in cardiovascular control. We also consider the current status, opportunities, and challenges of therapeutic modulation of HIF hydroxylases in the therapy of cardiovascular disease.
Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of ...hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.
Summary
Hypoxia is one of the hallmarks of the tumour microenvironment. It is the result of insufficient blood supply to support proliferating tumour cells. In response to hypoxia, the cellular ...machinery uses mechanisms whereby the low level of oxygen is sensed and counterbalanced by changing the transcription of numerous genes. Hypoxia‐inducible factors (HIF) play a critical role in the regulation of cellular responses to hypoxia. In recent years ample evidence has indicated that HIF play a prominent role in tumour immune responses. Up‐regulation of HIF1α promotes immune suppressive activity of myeloid‐derived suppressive cells (MDSC) and tumour‐associated macrophages (TAM) and rapid differentiation of MDSC to TAM. HIF1α does not affect MDSC differentiation to dendritic cells (DC) but instead causes DC activation. HIF inhibit effector functions of tumour‐infiltrating lymphocytes. HIF1α inhibits regulatory T (Treg) cell development by switching the balance towards T helper type 17 cells. However, as a major part of Treg cell differentiation does not take place in the tumour site, a functionally more important role of HIF1α is in the promotion of Treg cell recruitment to the tumour site in response to chemokines. As a result, the presence of Treg cells inside tumours is increased. Hence, HIF play a largely negative role in the regulation of immune responses inside tumours. It appears that therapeutic strategies targeting HIF in the immune system could be beneficial for anti‐tumour immune responses.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is ...potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)‐1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF‐1α‐overexpressing donor MSCs (HIF‐MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF‐MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF‐MSC than in MSC controls. The addition of Jagged1‐containing exosomes from MSC and HIF‐MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary‐like tube formation, and both processes were stimulated by HIF‐1α. Finally, subcutaneous injection of Jagged 1‐containing exosomes from MSC and HIF‐MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF‐MSC cultures. All Jagged1‐mediated effects could be blocked by prior incubation of exosomes with an anti‐Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF‐1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia‐related disease. Stem Cells 2017;35:1747–1759
Proposed model of angiogenesis induced in endothelial cells by Jagged‐1 loaded exosomes derived from mesenchymal stem cells overexpressing HIF‐1alpha.
Introduction: High altitude exposure results in acute hypoxia and an increase in the ventilatory drive. The aim of the current study was to examine the changes in gas exchange measures in a group of ...non-acclimated climbers during the ascent of Mt Kilimanjaro and immediately on return from altitude.
Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of ...the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O(2)-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. Induction of HIF activity under conditions of reduced O(2) availability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O(2) sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology.
Accumulating lines of experimental evidence have revealed that hypoxia‐inducible factors, HIF‐1α and HIF‐2α, are key regulators of the adaptation of cancer‐ and metastasis‐initiating cells and their ...differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin‐like growth factor‐1 receptor (IGF‐1R), stem cell factor (SCF) receptor KIT, transforming growth factor‐β receptors (TGF‐βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3′‐kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up‐regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency‐associated transcription factors (Oct‐3/4, Nanog and Sox‐2), glycolysis‐ and epithelial‐mesenchymal transition (EMT) programme‐associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self‐renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hypoxia‐inducible factor 1 (HIF‐1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF‐1 activity have ...been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF‐1 is eagerly desired for the development of novel anti‐cancer strategies. The importance of oxygen‐dependent and ubiquitin‐mediated proteolysis of the regulatory subunit of HIF‐1 (HIF‐1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF‐1α may become stable and active even under normoxic conditions; for example, when disease‐associated genetic and functional alterations in some genes trigger the aberrant activation of HIF‐1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms.
This article reviews the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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