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

ArticleinTrends in Pharmacological Sciences 33(4):207-14 · March 2012with36 Reads
DOI: 10.1016/j.tips.2012.01.005 · Source: PubMed
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.
    • "Quilamines are linked to linear polyamine vectors that use the polyamine transport system, which is overexpressed in most cancer cells [20]. Another dilemma linked with iron chelators is that iron depletion may inhibit prolyl hydroxylase domain (PHD) enzyme activity and therefore activate the hypoxia-inducible factor-1 (HIF-1) pathway, which is implicated in tumor aggressiveness and invasion [21] . Indeed , in both GBM cells, HIF-1α protein stabilization has been observed following DFX treatment in normoxic condition (Fig. 5 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Background Overcoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia. Results Under experimental normoxic condition (21 % O2), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3 % O2), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired. Conclusions Taken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application.
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    • "Furthermore , systematic analysis of the expression profiles of OSCC led to the identification of different tumor markers with prognostic value in OSCC, such as the carcinoembryonic antigen (CEA), carbonic anhydrase (CA) 19–9, CA 125, CA 15–3 and the squamous cell carcinoma (SCC) antigen [12]. Recently, also hypoxia-associated genes were identified as important markers for prognosis of OSCC [10, 13] suggesting that hypoxia-dependent pathways including the stabilization of HIF-1α play a key role in the development and progression of this disease [14][15][16]. So far, the expression and localization of HIF-1α, the key regulator of hypoxic responses, in OSCC cells have been determined by several groups, although the downstream effects in particular the expression of hypoxic pathways in the context of OSCC progression are widely unknown. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Changes in the tumor microenvironment and immune surveillance represent crucial hallmarks of various kinds of cancer, including oral squamous cell carcinoma (OSCC), and a close crosstalk of hypoxia regulating genes, an activation of chemokines and immune cells has been described. Methods: A review about the pivotal role of HIF-1, its crosstalk to various cornerstones in OSCC tumorigenesis is presented. Results: Hypoxia is a frequent event in OSCC and leads to a reprogramming of the cellular metabolism in order to prevent cell death. Hypoxic OSCC cells induce different adaptive changes such as anaerobic glycolysis, pH stabilisation and alterations of the gene and protein expression profile. This complex metabolic program is orchestrated by the hypoxia inducible factor (HIF)-1, the master regulator of early tumor progression. Hypoxia-dependent and -independent alterations in immune surveillance lead to different immune evasion strategies, which are partially mediated by alterations of the tumor cells, changes in the frequency, activity and repertoire of immune cell infiltrates and of soluble and environmental factors of the tumor micromilieu with consecutive generation of an immune escape phenotype, progression of disease and poor clinical outcome of OSCC patients. Conclusions: This review focusses on the importance of HIF-1 in the adaption and reprogramming of the metabolic system to reduced oxygen values as well as on the role of the tumor microenvironment for evasion of OSCC from immune recognition and destruction.
    Full-text · Article · Dec 2016
    • "For example, the normal conditional response of changing cell behavior and migrating away from regions of depleted resources is already built into the human genome. Hypoxia can trigger cell motility via HIF1α (Semenza 2012). A neoplastic cell need only activate and re-purpose this pathway to acquire the cell motility behavior that is central to tissue invasion and metastasis (Chen, Sprouffske, et al. 2011; Aktipis, Maley, et al. 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Evolution by natural selection is the conceptual foundation for nearly every branch of biology, and increasingly also for biomedicine and medical research. In cancer biology, evolution explains how populations of cells in tumors change over time. It is a fundamental question whether this evolutionary process is driven primarily by natural selection and adaptation, or by other evolutionary processes such as founder effects and drift. In cancer biology as in organismal evolutionary biology, there is controversy about this question, and also about the use of adaptation through natural selection as a guiding framework for research. In this paper, we discuss the differences and similarities between evolution among somatic cells versus evolution among organisms. We review what is known about the parameters and rate of evolution in neoplasms, as well as evidence for adaptation. We conclude that adaptation is a useful framework that accurately explains the defining characteristics of cancer. Further, convergent evolution through natural selection provides the only satisfying explanation both for how a group of diverse pathologies have enough in common to usefully share the descriptive label of 'cancer', and also for why this convergent condition becomes life-threatening.
    Full-text · Chapter · Nov 2016 · Journal of Translational Medicine
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