Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy

Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 03/2012; 33(4):207-14. DOI: 10.1016/
Source: PubMed

ABSTRACT Hypoxia-inducible factors (HIFs) mediate adaptive physiological responses to hypoxia. In human cancers that are accessible for O(2) electrode measurements, intratumoral hypoxia is common and severe hypoxia is associated with increased risk of mortality. HIF activity in regions of intratumoral hypoxia mediates angiogenesis, epithelial-mesenchymal transition, stem-cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy. A growing number of drugs have been identified that inhibit HIF activity by a variety of molecular mechanisms. Because many of these drugs are already FDA-approved for other indications, 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.

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    • "During hypoxia, or in case of VHL-gene mutations, HIFa subunits accumulates as a result of pVHL inability to determine their destruction, leading to stably up-regulation of hypoxia-response elements (HREs) such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), epidermal growth factor (EGF), and the glucose transporter, GLUT1 [12]. HIF transcriptional activity, especially HIF2a activity [13], mediates angiogenesis, epithelial– mesenchymal transition (EMT), stem-cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy in kidney cancer [14]. While HIF-1a and HIF-2a demonstrate overlapping effects on angiogenesis and ECM remodeling, they differ in controlling cell metabolism, proliferation, and oncogene activation in human ccRCCs [15]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 07/2015; DOI:10.1016/j.ctrv.2015.07.002 · 6.47 Impact Factor
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    • "This mechanism describes a natural selection of primary tumor cells with more radioresistant properties which have the ability to survive in harsh microenvironmental conditions induced by radiotherapy, such as hypoxia. As hypoxia resistance is a well-known property of metastatic cells [31] [32] [33], the induced radioresistance might go hand in hand with increased metastatic potential of surviving tumor cells. The hypothesis that radioresistance (be it intrinsic or induced) and metastatic potential might be related, is confirmed by the results of this study. "
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    ABSTRACT: Neoadjuvant chemoradiotherapy is used prior to surgery in curative treatment of esophageal cancer (EC). We evaluated the in-field control of this multimodal treatment by extraction of radiation dose parameters and determination of the spatial relation between tumor recurrence location(s) and radiation target volume (RTV). Treatment consisted of neoadjuvant chemotherapy (5-FU and cisplatin) and radiotherapy (36Gy) followed by Ivor-Lewis esophagectomy. For patients with locoregional recurrence(s), image fusion was performed between radiotherapy planning CT and follow-up CT(s). A region-of-interest was contoured on the planning CT around each locoregional recurrence. Mean and maximum radiation doses were then extracted to classify recurrences as out-of-field, marginal or in-field. Eighty patients were included. The median follow-up duration was 19months. Fifteen of 95 locoregional recurrences were detected in the RTV. These in-field relapses occurred in only 6 patients (7.8%) on 12 different anatomical locations. None of the patients with in-field failure had a pCR and all had concurrent distant failure on multiple anatomical sites. Neoadjuvant chemoradiotherapy followed by Ivor-Lewis esophagectomy yields excellent in-field control, as only a clear minority (7.8%) of patients developed a relapse in the RTV. In-field recurrence is associated with widespread tumor dissemination and poor pathological response to neoadjuvant treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Radiotherapy and Oncology 03/2015; 24(1). DOI:10.1016/j.radonc.2015.03.012 · 4.86 Impact Factor
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    • "The biological effects of radiation are highly influenced by O 2 levels, with hypoxia and anoxia making cells two to three times more resistant to radiation (Palcic et al., 1982; Marples et al., 1994b; Hockel and Vaupel, 2001; Ma et al., 2013). Tumor hypoxia, especially before radiotherapy, is known to be associated with poor clinical prognosis (Semenza, 2012). Hypoxia affects tumor development , metastatic capacity, and malignant progression, and results in resistance to therapy at doses above 1 Gy (Brown et al., 2010; Hanahan and Weinberg, 2011; Song et al., 2011). "
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    ABSTRACT: Low-dose hyper-radiosensitivity (HRS) has been reported in normal human lymphoblastoid cell lines for exposures at ≤ 20 cGy, but the cytogenetic effects of oxygen (O2 ) levels in tissue culture medium on HRS have not been evaluated. We asked whether HRS was lost in G2-irradiated cells grown in atmospheres of 2.5% or 5% O2 , compared to responses by cells cultured in ambient O2 (21%). The results indicate a loss of HRS when cells are cultured and irradiated either in 2.5% or 5% O2 . We then evaluated whether low O2 levels either before or after exposure were responsible for the loss of HRS. For cells irradiated in 5% O2 , subsequent immediate re-oxygenation to ambient O2 levels restored the HRS effect, while cells cultured and irradiated at ambient O2 levels and then transferred to 5% O2 exhibited little or no HRS, indicating that ambient O2 levels after, but not before, radiation substantially affect the amounts of cytogenetic damage. HRS was not observed when cells were irradiated in G1. At doses of 40-400 cGy there was significantly less cytogenetic damage when cells were recovering from radiation at low O2 levels than at ambient O2 levels. Here we provide the first cytogenetic evidence for the loss of HRS at low O2 levels in G2-irradiated cells; these results suggest that at low O2 levels for all doses evaluated there is either less damage to DNA, perhaps because of lower amounts of reactive oxygen species, or that DNA damage repair pathways are activated more efficiently. Environ. Mol. Mutagen., 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 03/2015; DOI:10.1002/em.21948 · 2.55 Impact Factor
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