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The Journal of Thoracic and... Jan 2014
Topics: Extracorporeal Membrane Oxygenation; Humans; Lung Transplantation; Oxygenators, Membrane; Respiratory Insufficiency
PubMed: 24199763
DOI: 10.1016/j.jtcvs.2013.08.079 -
Free Radical Biology & Medicine Sep 2023Reduced oxygen availability (hypoxia) can lead to cell and organ damage. Therefore, aerobic species depend on efficient mechanisms to counteract detrimental consequences... (Review)
Review
Reduced oxygen availability (hypoxia) can lead to cell and organ damage. Therefore, aerobic species depend on efficient mechanisms to counteract detrimental consequences of hypoxia. Hypoxia inducible factors (HIFs) and mitochondria are integral components of the cellular response to hypoxia and coordinate both distinct and highly intertwined adaptations. This leads to reduced dependence on oxygen, improved oxygen supply, maintained energy provision by metabolic remodeling and tapping into alternative pathways and increased resilience to hypoxic injuries. On one hand, many pathologies are associated with hypoxia and hypoxia can drive disease progression, for example in many cancer and neurological diseases. But on the other hand, controlled induction of hypoxia responses via HIFs and mitochondria can elicit profound health benefits and increase resilience. To tackle pathological hypoxia conditions or to apply health-promoting hypoxia exposures efficiently, cellular and systemic responses to hypoxia need to be well understood. Here we first summarize the well-established link between HIFs and mitochondria in orchestrating hypoxia-induced adaptations and then outline major environmental and behavioral modulators of their interaction that remain poorly understood.
Topics: Basic Helix-Loop-Helix Transcription Factors; Mitochondria; Cell Respiration; Humans; Animals; Temperature; Protein Stability; Altitude Sickness; Hypoxia; Diet; Oxygen; Environment
PubMed: 37385566
DOI: 10.1016/j.freeradbiomed.2023.06.015 -
Science Advances Nov 2023Poor oxygenation (hypoxia) is a common spatially heterogeneous feature of human tumors. Biological responses to tumor hypoxia are orchestrated by the decreased activity... (Review)
Review
Poor oxygenation (hypoxia) is a common spatially heterogeneous feature of human tumors. Biological responses to tumor hypoxia are orchestrated by the decreased activity of oxygen-dependent enzymes. The affinity of these enzymes for oxygen positions them along a continuum of oxygen sensing that defines their roles in launching reactive and adaptive cellular responses. These responses encompass regulation of all steps in the central dogma, with rapid perturbation of the metabolome and proteome followed by more persistent reprogramming of the transcriptome and epigenome. Core hypoxia response genes and pathways are commonly regulated at multiple inflection points, fine-tuning the dependencies on oxygen concentration and hypoxia duration. Ultimately, shifts in the activity of oxygen-sensing enzymes directly or indirectly endow cells with intrinsic hypoxia tolerance and drive processes that are associated with aggressive phenotypes in cancer including angiogenesis, migration, invasion, immune evasion, epithelial mesenchymal transition, and stemness.
Topics: Humans; Tumor Hypoxia; Neoplasms; Hypoxia; Oxygen; Phenotype
PubMed: 37992163
DOI: 10.1126/sciadv.adj6409 -
International Journal of Radiation... Mar 2019It has been known for over 100 years that tumor hypoxia, a near-universal characteristic of solid tumors, decreases the curative effectiveness of radiation therapy....
PURPOSE
It has been known for over 100 years that tumor hypoxia, a near-universal characteristic of solid tumors, decreases the curative effectiveness of radiation therapy. However, to date, there are no reports that demonstrate an improvement in radiation effectiveness in a mammalian tumor on the basis of tumor hypoxia localization and local hypoxia treatment.
METHODS AND MATERIALS
For radiation targeting of hypoxic subregions in mouse fibrosarcoma, we used oxygen images obtained using pulse electron paramagnetic resonance pO imaging combined with 3D-printed radiation blocks. This achieved conformal radiation delivery to all hypoxic areas in FSa fibrosarcomas in mice.
RESULTS
We demonstrate that treatment delivering a radiation boost to hypoxic volumes has a significant (P = .04) doubling of tumor control relative to boosts to well-oxygenated volumes. Additional dose to well-oxygenated tumor regions minimally increases tumor control beyond the 15% control dose to the entire tumor. If we can identify portions of the tumor that are more resistant to radiation, it might be possible to reduce the dose to more sensitive tumor volumes without significant compromise in tumor control.
CONCLUSIONS
This work demonstrates in a single, intact mammalian tumor type that tumor hypoxia is a local tumor phenomenon whose treatment can be enhanced by local radiation. Despite enormous clinical effort to overcome hypoxic radiation resistance, to our knowledge this is the first such demonstration, even in preclinical models, of targeting additional radiation to hypoxic tumor to improve the therapeutic ratio.
Topics: Animals; Cell Line, Tumor; Electron Spin Resonance Spectroscopy; Kaplan-Meier Estimate; Mice; Oxygen; Radiotherapy, Image-Guided; Tumor Hypoxia
PubMed: 30414912
DOI: 10.1016/j.ijrobp.2018.10.041 -
Scientific Reports Mar 2021Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply...
Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the "Warburg Effect". We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense.
Topics: Cell Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Models, Biological; Oxygen; Protein Stability; Stochastic Processes; Tumor Microenvironment
PubMed: 33707510
DOI: 10.1038/s41598-021-85184-8 -
Free Radical Biology & Medicine Dec 2017Molecular oxygen is one of the most important variables in modern cell culture systems. Fluctuations in its concentration can affect cell growth, differentiation,... (Review)
Review
Molecular oxygen is one of the most important variables in modern cell culture systems. Fluctuations in its concentration can affect cell growth, differentiation, signaling, and free radical production. In order to maintain culture viability, experimental validity, and reproducibility, it is imperative that oxygen levels be consistently maintained within physiological "normoxic" limits. Use of the term normoxia, however, is not consistent among scientists who experiment in cell culture. It is typically used to describe the atmospheric conditions of a standard incubator, not the true microenvironment to which the cells are exposed. This error may lead to the situation where cells grown in a standard "normoxic" oxygen concentration may actually be experiencing a wide range of conditions ranging from hyperoxia to near-anoxic conditions at the cellular level. This apparent paradox is created by oxygen's sluggish rate of diffusion through aqueous medium, and the generally underappreciated effects that cell density, media volume, and barometric pressure can have on pericellular oxygen concentration in a cell culture system. This review aims to provide an overview of this phenomenon we have termed "consumptive oxygen depletion" (COD), and includes a basic review of the physics, potential consequences, and alternative culture methods currently available to help circumvent this largely unrecognized problem.
Topics: Cell Count; Cell Culture Techniques; Cell Differentiation; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Diffusion; Humans; Hyperoxia; Oxygen; Oxygen Consumption; Reproducibility of Results; Translational Research, Biomedical
PubMed: 29032224
DOI: 10.1016/j.freeradbiomed.2017.10.003 -
The British Journal of Radiology Mar 2014Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review... (Review)
Review
Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review seeks to clarify the oxygen levels that are pertinent to this issue. It is argued that normoxia (20% oxygen) is an extremely poor comparator for "physoxia", i.e. the much lower levels of oxygen universally found in normal tissues, which averages about 5% oxygen, and ranges from about 3% to 7.4%. Importantly, it should be recognized that the median oxygenation in untreated tumours is significantly much lower, falling between approximately 0.3% and 4.2% oxygen, with most tumours exhibiting median oxygen levels <2%. This is partially dependent on the tissue of origin, and it is notable that many prostate and pancreatic tumours are profoundly hypoxic. In addition, therapy can induce even further, often unrecognized, changes in tumour oxygenation that may vary longitudinally, increasing or decreasing during treatment in ways that are not always predictable. Studies that fail to take cognizance of the actual physiological levels of oxygen in tissues (approximately 5%) and tumours (approximately 1%) may fail to identify the real circumstances driving tumour response to treatment and/or malignant progression. This can be of particular importance in genetic studies in vitro when comparison to human tumours is required.
Topics: Animals; Cell Hypoxia; Disease Progression; Humans; Hypoxia; Male; Neoplasms; Oxygen
PubMed: 24588669
DOI: 10.1259/bjr.20130676 -
Journal of Vascular Research 2014The metabolic regulation of blood flow is central to guaranteeing an adequate supply of blood to the tissues and microvascular network stability. It is assumed that... (Review)
Review
The metabolic regulation of blood flow is central to guaranteeing an adequate supply of blood to the tissues and microvascular network stability. It is assumed that vascular reactions to local oxygenation match blood supply to tissue demand via negative-feedback regulation. Low oxygen (O2) levels evoke vasodilatation, and thus an increase of blood flow and oxygen supply, by increasing (decreasing) the release of vasodilatory (vasoconstricting) metabolic signal substances with decreasing partial pressure of O2. This review analyses the principles of metabolic vascular control with a focus on the prevailing feedback regulations. We propose the following hypotheses with respect to vessel diameter adaptation. (1) In addition to O2-dependent signaling, metabolic vascular regulation can be effected by signal substances produced independently of local oxygenation (reflecting the presence of cells) due to the dilution effect. (2) Control of resting vessel tone, and thus perfusion reserve, could be explained by a vascular activity/hypoxia memory. (3) Vasodilator but not vasoconstrictor signaling can prevent shunt perfusion via signal conduction upstream to feeding arterioles. (4) For low perfusion heterogeneity in the steady state, metabolic signaling from the vessel wall or a perivascular tissue sleeve is optimal. (5) For amplification of perfusion during transient increases of tissue demand, red blood cell-derived vasodilators or vasoconstrictors diluted in flowing blood may be relevant.
Topics: Animals; Biomarkers; Cell Hypoxia; Energy Metabolism; Feedback, Physiological; Hemodynamics; Humans; Microvessels; Models, Cardiovascular; Oxygen; Regional Blood Flow; Signal Transduction
PubMed: 25531863
DOI: 10.1159/000369460 -
PloS One 2022Current methods for identification of oxygenator clotting during prolonged extracorporeal life support include visual inspection, evaluation of oxygenator resistance and...
Current methods for identification of oxygenator clotting during prolonged extracorporeal life support include visual inspection, evaluation of oxygenator resistance and oxygen exchange performance, and assessment of clotting-related laboratory parameters. However, these observations do not provide a quantitative assessment of oxygenator clot formation. By measuring changes in the dynamic oxygenator blood volume this study aimed to evaluate the relation to oxygenator resistance and oxygen transfer performance. Sixty-seven oxygenators were studied during adult extracorporeal life support. Oxygenator blood volume, oxygenator resistance, and oxygen transfer efficiency were monitored. Oxygenator blood volume decreased with increasing runtime (r = -0.462; p <0.001). There was a statistically significant, fair negative correlation between oxygenator blood volume and oxygenator resistance (r = -0.476; p<0.001) in all oxygenators, which became stronger analyzing only exchanged oxygenators (r = -0.680; p<0.001) and oxygenators with an oxygenator blood volume <187 mL (r = 0.831; p<0.001). No relevant correlation between oxygenator blood volume and O2 transfer was found. Oxygenator blood volume declined over time and was clearly associated with an increasing oxygenator resistance during prolonged extracorporeal life support, though O2 transfer was less affected.
Topics: Adult; Blood Volume; Carbon Dioxide; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Middle Aged; Monitoring, Physiologic; Oxygen; Oxygenators; Regional Blood Flow
PubMed: 35108345
DOI: 10.1371/journal.pone.0263360 -
Biotechnology Advances 2016In recent years, there has been great progress in the understanding of tumor biology and its surrounding microenvironment. Solid tumors create regions with low oxygen... (Review)
Review
In recent years, there has been great progress in the understanding of tumor biology and its surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of the cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems.
Topics: Animals; Cell Line, Tumor; Humans; Mice; Oxygen; Tumor Hypoxia; Tumor Microenvironment
PubMed: 27143654
DOI: 10.1016/j.biotechadv.2016.04.005