Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy
TL;DR: Clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.
About: This article is published in Trends in Pharmacological Sciences.The article was published on 2012-04-01 and is currently open access. It has received 1281 citations till now. The article focuses on the topics: Hypoxia-inducible factors & Hypoxia (medical).
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TL;DR: It is argued that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.
4,297 citations
Cites background from "Hypoxia-inducible factors: Mediator..."
...Subsequently, HIFa translocates to the nucleus and dimerizes with HIFb, regulating metabolic adaptation to hypoxia and the expression of pro-angiogenic genes such as vascular endothelial growth factor (VEGF) [62]....
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TL;DR: An approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden, and this systematic review discusses important pathways commonly targeted in cancer therapy.
Abstract: // Reza Bayat Mokhtari 1,2,4 , Tina S. Homayouni 1 , Narges Baluch 3 , Evgeniya Morgatskaya 1 , Sushil Kumar 1 , Bikul Das 4 and Herman Yeger 1,2 1 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada 4 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, USA Correspondence to: Herman Yeger, email: // Reza Bayat Mokhtari, email: // Keywords : Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), carbonic anhydrase inhibitor (CAI) Received : October 19, 2016 Accepted : February 27, 2017 Published : March 30, 2017 Abstract Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012.
1,270 citations
Cites background from "Hypoxia-inducible factors: Mediator..."
...VEGF acts by inducing angiogenesis in hypoxic conditions [119] and will be discussed in depth in the next section (Figure 2)....
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...There are many types of autocrine growth factors, with the major ones in cancer being vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor-2 (IGF-2), epidermal growth factor receptor (EGFR) and 5-hydroxytryptamine (5-HT; serotonin), to name a few [117-120]....
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TL;DR: Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.
Abstract: Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFĸB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.
1,231 citations
Cites background from "Hypoxia-inducible factors: Mediator..."
...Moreover, HIF-α contributes to cancer metastasis by altering cancer cell adhesion and motility through regulation of epithelial-to-mesenchymal transition (EMT) and E-cad, ZEB1, -2 and TCF3 expression,(58) as well as migration and invasion abilities through CXCR4,(59) CAIX,(60) LOX,(61) MMP-2, and MMP-9.(47,62,63)...
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...Moreover, the basal HIF-1a mRNA expression is regulated by NFKB in non-hypoxic conditions since HIF-1a promoter was shown to be responsive to certain NFKB subunits.39 The HIF pathway is required during physiological processes and is implicated in cancer biology by regulating hundreds of genes.47–49 This master regulator facilitates tumor growth by promoting angiogenesis via VEGF and SDF-1,50,51 metabolism via regulation of GLUT-1, GLUT-3, and glycolytic enzymes,52–54 and regulating cell apoptosis and cell survival via BNIP-3,55 p53,56,57 TGF-β, and bFGF.3 Moreover, HIF-α contributes to cancer metastasis by altering cancer cell adhesion and motility through regulation of epithelial-to-mesenchymal transition (EMT) and E-cad, ZEB1, -2 and TCF3 expression,58 as well as migration and invasion abilities through CXCR4,59 CAIX,60 LOX,61 MMP-2, and MMP-9....
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TL;DR: A direct link between hypoxia and the composition and the organization of the ECM is established, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.
Abstract: Of the deaths attributed to cancer, 90% are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that hypoxia and the extracellular matrix (ECM) might have crucial roles in metastasis. During tumour evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence tumour and stromal cell properties, such as proliferation and motility. Originally thought of as independent contributors to metastatic spread, recent studies have established a direct link between hypoxia and the composition and the organization of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.
1,034 citations
TL;DR: How cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression is discussed; in particular, potential metabolic vulnerabilities that might be targeted therapeutically are highlighted.
Abstract: Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.
982 citations
References
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TL;DR: HIF-1 is implicate in the activation of VEGF transcription in hypoxic cells and this work demonstrates the involvement of Hif-1 in theactivation of V EGF transcription.
Abstract: Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.
3,709 citations
TL;DR: HIF plays a central role in the transcriptional response to changes in oxygen availability and is modulated by FIH1-mediated asparagine hydroxylation, and HIF-modulatory drugs are now being developed for diverse diseases.
2,623 citations
TL;DR: It is reported that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis.
2,303 citations
TL;DR: In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors, and the HIFα subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1α, sirtuins, and metabolites.
1,919 citations
TL;DR: It is reported that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors.
1,733 citations