Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter
Abstract
Simple Summary
Abstract
1. Introduction
2. Finding the Appropriate Model System
3. Quantification of Hypoxia Levels
3.1. Invasive Methods
3.2. Non-Invasive Imaging for Preclinical Studies
3.3. Medical Imaging
4. Biological Significance of Hypoxia Levels
4.1. Hypoxia Sensing at Mild and Moderate Levels
4.2. Boosting of Selected Activities at Mild and Moderate Hypoxia
4.3. Overall Shut Down and Activation of Survival Strategies at Severe Hypoxia
5. Involvement of the Tumor Microenvironment
5.1. Epithelial-Mesenchymal Transition (EMT), Migration and Invasion
5.2. Angiogenesis
5.3. Inflammation and Immune Evasion
6. Perspectives
6.1. Advancing Biological Understanding of Hypoxia Levels
6.1.1. Multiparametric and Multimodality Imaging
6.1.2. Molecular Characterization of Tumor Samples
6.2. New Treatment Options
6.2.1. Radiation Delivery Techniques
6.2.2. Combination Therapies with Hypoxia Targeting Drugs
6.2.3. Immunotherapy and Combination Therapy with Radiation
7. Conclusions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Horsman, M.R.; Vaupel, P. Pathophysiological Basis for the Formation of the Tumor Microenvironment. Front. Oncol. 2016, 6, 66. [Google Scholar] [CrossRef] [PubMed]
- Bader, S.B.; Dewhirst, M.W.; Hammond, E.M. Cyclic Hypoxia: An Update on Its Characteristics, Methods to Measure It and Biological Implications in Cancer. Cancers 2020, 13, 23. [Google Scholar] [CrossRef] [PubMed]
- Grimes, D.R.; Partridge, M. A mechanistic investigation of the oxygen fixation hypothesis and oxygen enhancement ratio. Biomed. Phys. Eng. Express 2015, 1. [Google Scholar] [CrossRef]
- Hockel, M.; Vaupel, P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst. 2001, 93, 266–276. [Google Scholar] [CrossRef] [PubMed]
- Vaupel, P.; Hockel, M.; Mayer, A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal. 2007, 9, 1221–1235. [Google Scholar] [CrossRef] [PubMed]
- Bracken, C.P.; Fedele, A.O.; Linke, S.; Balrak, W.; Lisy, K.; Whitelaw, M.L.; Peet, D.J. Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment. J. Biol. Chem. 2006, 281, 22575–22585. [Google Scholar] [CrossRef]
- Jiang, B.H.; Semenza, G.L.; Bauer, C.; Marti, H.H. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol. Cell Physiol. 1996, 271, C1172–C1180. [Google Scholar] [CrossRef]
- Thomlinson, R.H.; Gray, L.H. The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy. Br. J. Cancer 1955, 9, 539–549. [Google Scholar] [CrossRef]
- Gatenby, R.A.; Kessler, H.B.; Rosenblum, J.S.; Coia, L.R.; Moldofsky, P.J.; Hartz, W.H.; Broder, G.J. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 1988, 14, 831–838. [Google Scholar] [CrossRef]
- Horsman, M.R.; Mortensen, L.S.; Petersen, J.B.; Busk, M.; Overgaard, J. Imaging hypoxia to improve radiotherapy outcome. Nat. Rev. Clin. Oncol. 2012, 9, 674–687. [Google Scholar] [CrossRef]
- Zhang, Q.; Yan, Q.; Yang, H.F.; Wei, W.Y. Oxygen sensing and adaptability won the 2019 Nobel Prize in Physiology or medicine. Genes Dis. 2019, 6, 328–332. [Google Scholar] [CrossRef] [PubMed]
- Casazza, A.; Di Conza, G.; Wenes, M.; Finisguerra, V.; Deschoemaeker, S.; Mazzone, M. Tumor stroma: A complexity dictated by the hypoxic tumor microenvironment. Oncogene 2014, 33, 1743–1754. [Google Scholar] [CrossRef] [PubMed]
- Jin, M.Z.; Jin, W.L. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct. Target. Ther. 2020, 5. [Google Scholar] [CrossRef] [PubMed]
- Krisnawan, V.E.; Stanley, J.A.; Schwarz, J.K.; DeNardo, D.G. Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance. Cancers 2020, 12, 2916. [Google Scholar] [CrossRef]
- Pavlacky, J.; Polak, J. Technical Feasibility and Physiological Relevance of Hypoxic Cell Culture Models. Front. Endocrinol. 2020, 11, 57. [Google Scholar] [CrossRef]
- Place, T.L.; Domann, F.E.; Case, A.J. Limitations of oxygen delivery to cells in culture: An underappreciated problem in basic and translational research. Free Radic. Biol. Med. 2017, 113, 311–322. [Google Scholar] [CrossRef] [PubMed]
- Kugeratski, F.G.; Atkinson, S.J.; Neilson, L.J.; Lilla, S.; Knight, J.R.P.; Serneels, J.; Juin, A.; Ismail, S.; Bryant, D.M.; Markert, E.K.; et al. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Sci. Signal. 2019, 12, eaan8247. [Google Scholar] [CrossRef]
- Carmona-Fontaine, C.; Deforet, M.; Akkari, L.; Thompson, C.B.; Joyce, J.A.; Xavier, J.B. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl. Acad. Sci. USA 2017, 114, 2934–2939. [Google Scholar] [CrossRef]
- Campillo, N.; Falcones, B.; Otero, J.; Colina, R.; Gozal, D.; Navajas, D.; Farré, R.; Almendros, I. Differential Oxygenation in Tumor Microenvironment Modulates Macrophage and Cancer Cell Crosstalk: Novel Experimental Setting and Proof of Concept. Front. Oncol. 2019, 9, 43. [Google Scholar] [CrossRef]
- Leedale, J.; Herrmann, A.; Bagnall, J.; Fercher, A.; Papkovsky, D.; See, V.; Bearon, R.N. Modeling the dynamics of hypoxia inducible factor-1α (HIF-1α) within single cells and 3D cell culture systems. Math. Biosci. 2014, 258, 33–43. [Google Scholar] [CrossRef]
- Fiorini, E.; Veghini, L.; Corbo, V. Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple. Front. Cell Dev. Biol. 2020, 8, 166. [Google Scholar] [CrossRef] [PubMed]
- Riffle, S.; Pandey, R.N.; Albert, M.; Hegde, R.S. Linking hypoxia, DNA damage and proliferation in multicellular tumor spheroids. BMC Cancer 2017, 17, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Rodenhizer, D.; Gaude, E.; Cojocari, D.; Mahadevan, R.; Frezza, C.; Wouters, B.G.; McGuigan, A.P. A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients. Nat. Mater. 2016, 15, 227–234. [Google Scholar] [CrossRef] [PubMed]
- Bhattacharya, S.; Calar, K.; de la Puente, P. Mimicking tumor hypoxia and tumor-immune interactions employing three-dimensional in vitro models. J. Exp. Clin. Cancer Res. 2020, 39. [Google Scholar] [CrossRef] [PubMed]
- Day, C.P.; Merlino, G.; Van Dyke, T. Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges. Cell 2015, 163, 39–53. [Google Scholar] [CrossRef]
- Vaupel, P.; Schlenger, K.; Knoop, C.; Hockel, M. Oxygenation of human tumors: Evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991, 51, 3316–3322. [Google Scholar]
- Hillestad, T.; Hompland, T.; Fjeldbo, C.S.; Skingen, V.E.; Salberg, U.B.; Aarnes, E.-K.; Nilsen, A.; Lund, K.V.; Evensen, T.S.; Kristensen, G.B.; et al. MRI Distinguishes Tumor Hypoxia Levels of Different Prognostic and Biological Significance in Cervical Cancer. Cancer Res. 2020, 80, 3993–4003. [Google Scholar] [CrossRef]
- Russell, J.; Carlin, S.; Burke, S.A.; Wen, B.; Yang, K.M.; Ling, C.C. Immunohistochemical detection of changes in tumor hypoxia. Int. J. Radiat. Oncol. Biol. Phys. 2009, 73, 1177–1186. [Google Scholar] [CrossRef]
- Urtasun, R.C.; Chapman, J.D.; Raleigh, J.A.; Franko, A.J.; Koch, C.J. Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia. Int. J. Radiat. Oncol. Biol. Phys. 1986, 12, 1263–1267. [Google Scholar] [CrossRef]
- Gross, M.W.; Karbach, U.; Groebe, K.; Franko, A.J.; Mueller-Klieser, W. Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids. Int. J. Cancer 1995, 61, 567–573. [Google Scholar] [CrossRef]
- Raleigh, J.A.; Chou, S.C.; Arteel, G.E.; Horsman, M.R. Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat. Res. 1999, 151, 580–589. [Google Scholar] [CrossRef] [PubMed]
- Koch, C.J. Importance of antibody concentration in the assessment of cellular hypoxia by flow cytometry: EF5 and pimonidazole. Radiat. Res. 2008, 169, 677–688. [Google Scholar] [CrossRef]
- Zaidi, M.; Fu, F.; Cojocari, D.; McKee, T.D.; Wouters, B.G. Quantitative Visualization of Hypoxia and Proliferation Gradients Within Histological Tissue Sections. Front. Bioeng. Biotechnol. 2019, 7, 397. [Google Scholar] [CrossRef] [PubMed]
- Hoogsteen, I.J.; Marres, H.A.M.; van den Hoogen, F.J.A.; Rijken, P.F.J.W.; Lok, J.; Bussink, J.; Kaanders, J.H.A.M. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance. Int. J. Radiat. Oncol. 2012, 84, 807–814. [Google Scholar] [CrossRef] [PubMed]
- Sobhanifar, S.; Aquino-Parsons, C.; Stanbridge, E.J.; Olive, P.L. Reduced expression of hypoxia-inducible factor-1α in perinecrotic regions of solid tumors. Cancer Res. 2005, 65, 7259–7266. [Google Scholar] [CrossRef] [PubMed]
- Mayer, A.; Höckel, M.; Vaupel, P. Endogenous hypoxia markers: Case not proven! Adv. Exp. Med. Biol. 2008, 614, 127–136. [Google Scholar] [CrossRef]
- Chen, J.L.Y.; Lucas, J.E.; Schroeder, T.; Mori, S.; Wu, J.L.; Nevins, J.; Dewhirst, M.; West, M.; Chi, J.T. The Genomic Analysis of Lactic Acidosis and Acidosis Response in Human Cancers. PLoS Genet. 2008, 4, e1000293. [Google Scholar] [CrossRef]
- Sorensen, B.S.; Toustrup, K.; Horsman, M.R.; Overgaard, J.; Alsner, J. Identifying pH independent hypoxia induced genes in human squamous cell carcinomas in vitro. Acta Oncol. 2010, 49, 895–905. [Google Scholar] [CrossRef]
- Rupp, N.J.; Schüffler, P.J.; Zhong, Q.; Falkner, F.; Rechsteiner, M.; Rüschoff, J.H.; Fankhauser, C.; Drach, M.; Largo, R.; Tremp, M.; et al. Oxygen supply maps for hypoxic microenvironment visualization in prostate cancer. J. Pathol. Inform. 2016, 7, 3. [Google Scholar] [CrossRef]
- Yang, L.; West, C.M. Hypoxia gene expression signatures as predictive biomarkers for personalising radiotherapy. Br. J. Radiol. 2019, 92, 20180036. [Google Scholar] [CrossRef]
- Toustrup, K.; Sorensen, B.S.; Nordsmark, M.; Busk, M.; Wiuf, C.; Alsner, J.; Overgaard, J. Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer. Cancer Res. 2011, 71, 5923–5931. [Google Scholar] [CrossRef] [PubMed]
- Ragnum, H.B.; Vlatkovic, L.; Lie, A.K.; Axcrona, K.; Julin, C.H.; Frikstad, K.M.; Hole, K.H.; Seierstad, T.; Lyng, H. The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. Br. J. Cancer 2015, 112, 382–390. [Google Scholar] [CrossRef] [PubMed]
- Fjeldbo, C.S.; Julin, C.H.; Lando, M.; Forsberg, M.F.; Aarnes, E.K.; Alsner, J.; Kristensen, G.B.; Malinen, E.; Lyng, H. Integrative Analysis of DCE-MRI and Gene Expression Profiles in Construction of a Gene Classifier for Assessment of Hypoxia-Related Risk of Chemoradiotherapy Failure in Cervical Cancer. Clin. Cancer Res. 2016, 22, 4067–4076. [Google Scholar] [CrossRef] [PubMed]
- Cao, X.; Allu, S.R.; Jiang, S.; Gunn, J.R.; Yao, C.; Xin, J.; Bruza, P.; Gladstone, D.J.; Jarvis, L.A.; Tian, J.; et al. High-resolution pO2 imaging improves quantification of the hypoxic fraction in tumors during radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 2020, 109, 603–613. [Google Scholar] [CrossRef] [PubMed]
- Vinogradov, S.A.; Lo, L.W.; Jenkins, W.T.; Evans, S.M.; Koch, C.; Wilson, D.F. Noninvasive imaging of the distribution in oxygen in tissue in vivo using near-infrared phosphors. Biophys. J. 1996, 70, 1609–1617. [Google Scholar] [CrossRef]
- Rytelewski, M.; Haryutyunan, K.; Nwajei, F.; Shanmugasundaram, M.; Wspanialy, P.; Zal, M.A.; Chen, C.-H.; El Khatib, M.; Plunkett, S.; Vinogradov, S.A.; et al. Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors. J. Immunother. Cancer 2019, 7, 78. [Google Scholar] [CrossRef]
- Cao, X.; Rao Allu, S.; Jiang, S.; Jia, M.; Gunn, J.R.; Yao, C.; LaRochelle, E.P.; Shell, J.R.; Bruza, P.; Gladstone, D.J.; et al. Tissue pO2 distributions in xenograft tumors dynamically imaged by Cherenkov-excited phosphorescence during fractionated radiation therapy. Nat. Commun. 2020, 11, 573–579. [Google Scholar] [CrossRef]
- Helmlinger, G.; Yuan, F.; Dellian, M.; Jain, R.K. Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat. Med. 1997, 3, 177–182. [Google Scholar] [CrossRef]
- Zheng, X.; Cui, L.; Chen, M.; Soto, L.A.; Graves, E.E.; Rao, J. A Near-Infrared Phosphorescent Nanoprobe Enables Quantitative, Longitudinal Imaging of Tumor Hypoxia Dynamics during Radiotherapy. Cancer Res. 2019, 79, 4787–4797. [Google Scholar] [CrossRef]
- Zheng, X.; Mao, H.; Huo, D.; Wu, W.; Liu, B.; Jiang, X. Successively activatable ultrasensitive probe for imaging tumour acidity and hypoxia. Nat. Biomed. Eng. 2017, 1, 1–9. [Google Scholar] [CrossRef]
- Matsumoto, S.; Saito, K.; Yasui, H.; Morris, H.D.; Munasinghe, J.P.; Lizak, M.; Merkle, H.; Larsen, J.H.A.; Choudhuri, R.; Devasahayam, N.; et al. EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate. Magn. Reson. Med. 2013, 69, 1443–1450. [Google Scholar] [CrossRef] [PubMed]
- Busk, M.; Horsman, M.R.; Overgaard, J. Resolution in PET hypoxia imaging: Voxel size matters. Acta Oncol. 2008, 47, 1201–1210. [Google Scholar] [CrossRef] [PubMed]
- Grimes, D.R.; Warren, D.R.; Warren, S. Hypoxia imaging and radiotherapy: Bridging the resolution gap. Br. J. Radiol. 2017, 90, 20160939. [Google Scholar] [CrossRef] [PubMed]
- Chakhoyan, A.; Guillamo, J.-S.; Collet, S.; Kauffmann, F.; Delcroix, N.; Lechapt-Zalcman, E.; Constans, J.-M.; Petit, E.; MacKenzie, E.T.; Barré, L.; et al. FMISO-PET-derived brain oxygen tension maps: Application to glioblastoma and less aggressive gliomas. Sci. Rep. 2017, 7, 10210. [Google Scholar] [CrossRef] [PubMed]
- Toma-Daşu, I.; Uhrdin, J.; Antonovic, L.; Daşu, A.; Nuyts, S.; Dirix, P.; Haustermans, K.; Brahme, A. Dose prescription and treatment planning based on FMISO-PET hypoxia. Acta Oncol. 2012, 51, 222–230. [Google Scholar] [CrossRef]
- Toma-Daşu, I.; Daşu, A.; Brahme, A. Quantifying tumour hypoxia by PET imaging—A theoretical analysis. Adv. Exp. Med. Biol. 2009, 645, 267–272. [Google Scholar] [CrossRef]
- Casciari, J.J.; Rasey, J.S. Determination of the Radiobiologically Hypoxic Fraction in Multicellular Spheroids from Data on the Uptake of [H-3] Fluoromisonidazole. Radiat. Res. 1995, 141, 28–36. [Google Scholar] [CrossRef]
- Rasey, J.S.; Koh, W.J.; Grierson, J.R.; Grunbaum, Z.; Krohn, K.A. Radiolabeled Fluoromisonidazole as an Imaging Agent for Tumor Hypoxia. Int. J. Radiat. Oncol. 1989, 17, 985–991. [Google Scholar] [CrossRef]
- Warren, D.R.; Partridge, M. The role of necrosis, acute hypoxia and chronic hypoxia in F-18-FMISO PET image contrast: A computational modelling study. Phys. Med. Biol. 2016, 61, 8596–8624. [Google Scholar] [CrossRef]
- O’Connor, J.P.B.; Robinson, S.P.; Waterton, J.C. Imaging tumour hypoxia with oxygen-enhanced MRI and BOLD MRI. Br. J. Radiol. 2019, 92, 20180642. [Google Scholar] [CrossRef]
- Lyng, H.; Malinen, E. Hypoxia in cervical cancer: From biology to imaging. Clin. Transl. Imaging 2017, 5, 373–388. [Google Scholar] [CrossRef]
- Hompland, T.; Hole, K.H.; Ragnum, H.B.; Aarnes, E.-K.; Vlatkovic, L.; Lie, A.K.; Patzke, S.; Brennhovd, B.; Seierstad, T.; Lyng, H. Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients. Cancer Res. 2018, 78, 4774–4785. [Google Scholar] [CrossRef]
- Jardim-Perassi, B.V.; Huang, S.; Dominguez-Viqueira, W.; Poleszczuk, J.; Budzevich, M.M.; Abdalah, M.A.; Pillai, S.R.; Ruiz, E.; Bui, M.M.; Zuccari, D.A.P.C.; et al. Multiparametric MRI and Coregistered Histology Identify Tumor Habitats in Breast Cancer Mouse Models. Cancer Res. 2019, 79, 3952–3964. [Google Scholar] [CrossRef]
- Kafri, M.; Metzl-Raz, E.; Jona, G.; Barkai, N. The Cost of Protein Production. Cell Rep. 2016, 14, 22–31. [Google Scholar] [CrossRef]
- Ast, T.; Mootha, V.K. Oxygen and mammalian cell culture: Are we repeating the experiment of Dr. Ox? Nat. Metab. 2019, 1, 858–860. [Google Scholar] [CrossRef]
- Bertout, J.A.; Patel, S.A.; Simon, M.C. The impact of O2 availability on human cancer. Nat. Rev. Cancer 2008, 8, 967–975. [Google Scholar] [CrossRef] [PubMed]
- Tian, Y.M.; Yeoh, K.K.; Lee, M.K.; Eriksson, T.; Kessler, B.M.; Kramer, H.B.; Edelmann, M.J.; Willam, C.; Pugh, C.W.; Schofield, C.J.; et al. Differential Sensitivity of Hypoxia Inducible Factor Hydroxylation Sites to Hypoxia and Hydroxylase Inhibitors. J. Biol. Chem. 2011, 286, 13041–13051. [Google Scholar] [CrossRef]
- Iommarini, L.; Porcelli, A.M.; Gasparre, G.; Kurelac, I. Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1α in Cancer. Front. Oncol. 2017, 7, 286. [Google Scholar] [CrossRef] [PubMed]
- Hutchison, G.J.; Valentine, H.R.; Loncaster, J.A.; Davidson, S.E.; Hunter, R.D.; Roberts, S.A.; Harris, A.L.; Stratford, I.J.; Price, P.M.; West, C.M.L. Hypoxia-inducible factor lα expression as an intrinsic marker of hypoxia: Correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix. Clin. Cancer Res. 2004, 10, 8405–8412. [Google Scholar] [CrossRef] [PubMed]
- Mayer, A.; Hockel, M.; Wree, A.; Leo, C.; Horn, L.C.; Vaupel, P. Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia. Cancer Res. 2008, 68, 4719–4726. [Google Scholar] [CrossRef]
- Ragnum, H.B.; Roe, K.; Holm, R.; Vlatkovic, L.; Nesland, J.M.; Aarnes, E.K.; Ree, A.H.; Flatmark, K.; Seierstad, T.; Lilleby, W.; et al. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer. Int. J. Radiat. Oncol. 2013, 87, 753–760. [Google Scholar] [CrossRef] [PubMed]
- Maynard, M.A.; Ohh, M. von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am. J. Nephrol. 2004, 24, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Batie, M.; Rocha, S. Gene transcription and chromatin regulation in hypoxia. Biochem. Soc. Trans. 2020, 48, 1121–1128. [Google Scholar] [CrossRef] [PubMed]
- Tausendschon, M.; Dehne, N.; Brune, B. Hypoxia causes epigenetic gene regulation in macrophages by attenuating Jumonji histone demethylase activity. Cytokine 2011, 53, 256–262. [Google Scholar] [CrossRef] [PubMed]
- Batie, M.; Frost, J.; Frost, M.; Wilson, J.W.; Schofield, P.; Rocha, S. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 2019, 363, 1222–1226. [Google Scholar] [CrossRef]
- Chakraborty, A.A.; Laukka, T.; Myllykoski, M.; Ringel, A.E.; Booker, M.A.; Tolstorukov, M.Y.; Meng, Y.J.; Meier, S.R.; Jennings, R.B.; Creech, A.L.; et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 2019, 363, 1217–1222. [Google Scholar] [CrossRef]
- Guzy, R.D.; Schumacker, P.T. Oxygen sensing by mitochondria at complex III: The paradox of increased reactive oxygen species during hypoxia. Exp. Physiol. 2006, 91, 807–819. [Google Scholar] [CrossRef]
- Klimova, T.; Chandel, N.S. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 2008, 15, 660–666. [Google Scholar] [CrossRef]
- Waypa, G.B.; Smith, K.A.; Schumacker, P.T. O2 sensing, mitochondria and ROS signaling: The fog is lifting. Mol. Asp. Med. 2016, 47, 76–89. [Google Scholar] [CrossRef]
- Li, P.Y.; Wu, M.L.; Wang, J.; Sui, Y.L.; Liu, S.L.; Shi, D.Y. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells. Redox Biol. 2016, 8, 91–97. [Google Scholar] [CrossRef]
- Lluis, J.M.; Buricchi, F.; Chiarugi, P.; Morales, A.; Fernandez-Checa, J.C. Dual role of mitochondrial reactive oxygen species in hypoxia signaling: Activation of nuclear factor-κ B via c-SRC- and oxidant-dependent cell death. Cancer Res. 2007, 67, 7368–7377. [Google Scholar] [CrossRef] [PubMed]
- Schroedl, C.; McClintock, D.S.; Budinger, G.R.S.; Chandel, N.S. Hypoxic but not anoxic stabilization of HIF-1α requires mitochondrial reactive oxygen species. Am. J. Physiol. Lung Cell. Mol. Physiol. 2002, 283, L922–L931. [Google Scholar] [CrossRef] [PubMed]
- Hamanaka, R.B.; Weinberg, S.E.; Reczek, C.R.; Chandel, N.S. The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia. Cell Rep. 2016, 15, 451–459. [Google Scholar] [CrossRef] [PubMed]
- Sabharwal, S.S.; Waypa, G.B.; Marks, J.D.; Schumacker, P.T. Peroxiredoxin-5 targeted to the mitochondrial intermembrane space attenuates hypoxia-induced reactive oxygen species signalling. Biochem. J. 2013, 456, 337–346. [Google Scholar] [CrossRef] [PubMed]
- Goyal, P.; Weissmann, N.; Grimminger, F.; Hegel, C.; Bader, L.; Rose, F.; Fink, L.; Ghofrani, H.A.; Schermuly, R.T.; Schmidt, H.H.H.W.; et al. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxiainducible factor 1 via increase in reactive oxygen species. Free Radic. Biol. Med. 2004, 36, 1279–1288. [Google Scholar] [CrossRef] [PubMed]
- Li, F.; Sonveaux, P.; Rabbani, Z.N.; Liu, S.L.; Yan, B.; Huang, Q.; Vujaskovic, Z.; Dewhirst, M.W.; Li, C.Y. Regulation of HIF-1α stability through S-nitrosylation. Mol. Cell 2007, 26, 63–74. [Google Scholar] [CrossRef]
- Moon, E.J.; Sonveaux, P.; Porporato, P.E.; Danhier, P.; Gallez, B.; Batinic-Haberle, I.; Nien, Y.C.; Schroeder, T.; Dewhirst, M.W. NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment. Proc. Natl. Acad. Sci. USA 2010, 107, 20477–20482. [Google Scholar] [CrossRef]
- Nanduri, J.; Vaddi, D.R.; Khan, S.A.; Wang, N.; Makarenko, V.; Semenza, G.L.; Prabhakar, N.R. HIF-1α Activation by Intermittent Hypoxia Requires NADPH Oxidase Stimulation by Xanthine Oxidase. PLoS ONE 2015, 10, e0119762. [Google Scholar] [CrossRef][Green Version]
- Cao, Y.T.; Eble, J.M.; Moon, E.; Yuan, H.; Weitzel, D.H.; Landon, C.D.; Nien, C.Y.C.; Hanna, G.; Rich, J.N.; Provenzale, J.M.; et al. Tumor Cells Upregulate Normoxic HIF-1α in Response to Doxorubicin. Cancer Res. 2013, 73, 6230–6242. [Google Scholar] [CrossRef]
- Mungai, P.T.; Waypa, G.B.; Jairaman, A.; Prakriya, M.; Dokic, D.; Ball, M.K.; Schumacker, P.T. Hypoxia Triggers AMPK Activation through Reactive Oxygen Species-Mediated Activation of Calcium Release-Activated Calcium Channels. Mol. Cell. Biol. 2011, 31, 3531–3545. [Google Scholar] [CrossRef]
- Arsham, A.M.; Howell, J.J.; Simon, M.C. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 2003, 278, 29655–29660. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.P.; Cash, T.P.; Jones, R.G.; Keith, B.; Thompson, C.B.; Simon, M.C. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 2006, 21, 521–531. [Google Scholar] [CrossRef] [PubMed]
- Chee, N.T.; Lohse, I.; Brothers, S.P. mRNA-to-protein translation in hypoxia. Mol. Cancer 2019, 18. [Google Scholar] [CrossRef]
- Ho, J.J.D.; Wang, M.L.; Audas, T.E.; Kwon, D.; Carlsson, S.K.; Timpano, S.; Evagelou, S.L.; Brothers, S.; Gonzalgo, M.L.; Krieger, J.R.; et al. Systemic Reprogramming of Translation Efficiencies on Oxygen Stimulus. Cell Rep. 2016, 14, 1293–1300. [Google Scholar] [CrossRef] [PubMed]
- Staudacher, J.J.; Naarmann-de Vries, I.S.; Ujvari, S.J.; Klinger, B.; Kasim, M.; Benko, E.; Ostareck-Lederer, A.; Ostareck, D.H.; Persson, A.B.; Lorenzen, S.; et al. Hypoxia-induced gene expression results from selective mRNA partitioning to the endoplasmic reticulum. Nucleic Acids Res. 2015, 43, 3219–3236. [Google Scholar] [CrossRef]
- Uniacke, J.; Holterman, C.E.; Lachance, G.; Franovic, A.; Jacob, M.D.; Fabian, M.R.; Payette, J.; Holcik, M.; Pause, A.; Lee, S. An oxygen-regulated switch in the protein synthesis machinery. Nature 2012, 486, 126–129. [Google Scholar] [CrossRef]
- Kennedy, F.G.; Jones, D.P. Oxygen dependence of mitochondrial function in isolated rat cardiac myocytes. Am. J. Physiol. Cell Physiol. 1986, 250, C374–C383. [Google Scholar] [CrossRef]
- Wilson, D.F.; Rumsey, W.L.; Green, T.J.; Vanderkooi, J.M. The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J. Biol. Chem. 1988, 263, 2712–2718. [Google Scholar] [CrossRef]
- Scandurra, F.M.; Gnaiger, E. Cell respiration under hypoxia: Facts and artefacts in mitochondrial oxygen kinetics. Adv. Exp. Med. Biol. 2010, 662, 7–25. [Google Scholar] [CrossRef]
- Clavo, A.C.; Brown, R.S.; Wahl, R.L. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J. Nucl. Med. 1995, 36, 1625–1632. [Google Scholar]
- Turkcan, S.; Kiru, L.; Naczynski, D.J.; Sasportas, L.S.; Pratx, G. Lactic Acid Accumulation in the Tumor Microenvironment Suppresses (18)F-FDG Uptake. Cancer Res. 2019, 79, 410–419. [Google Scholar] [CrossRef]
- Iyer, N.V.; Kotch, L.E.; Agani, F.; Leung, S.W.; Laughner, E.; Wenger, R.H.; Gassmann, M.; Gearhart, J.D.; Lawler, A.M.; Yu, A.Y.; et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 1998, 12, 149–162. [Google Scholar] [CrossRef] [PubMed]
- Sorensen, B.S.; Hao, J.; Overgaard, J.; Vorum, H.; Honore, B.; Alsner, J.; Horsman, M.R. Influence of oxygen concentration and pH on expression of hypoxia induced genes. Radiother. Oncol. 2005, 76, 187–193. [Google Scholar] [CrossRef] [PubMed]
- Sorensen, B.S.; Horsman, M.R.; Vorum, H.; Honore, B.; Overgaard, J.; Alsner, J. Proteins upregulated by mild and severe hypoxia in squamous cell carcinomas in vitro identified by proteomics. Radiother. Oncol. 2009, 92, 443–449. [Google Scholar] [CrossRef] [PubMed]
- Perez de Heredia, F.; Wood, I.S.; Trayhurn, P. Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflugers Arch. 2010, 459, 509–518. [Google Scholar] [CrossRef]
- Airley, R.; Loncaster, J.; Davidson, S.; Bromley, M.; Roberts, S.; Patterson, A.; Hunter, R.; Stratford, I.; West, C. Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin. Cancer Res. 2001, 7, 928–934. [Google Scholar]
- Rademakers, S.E.; Lok, J.; van der Kogel, A.J.; Bussink, J.; Kaanders, J.H. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer 2011, 11, 167. [Google Scholar] [CrossRef]
- Xiang, L.; Mou, J.; Shao, B.; Wei, Y.; Liang, H.; Takano, N.; Semenza, G.L.; Xie, G. Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis. 2019, 10, 40. [Google Scholar] [CrossRef]
- Fulda, S.; Debatin, K.M. HIF-1-regulated glucose metabolism: A key to apoptosis resistance? Cell Cycle 2007, 6, 790–792. [Google Scholar] [CrossRef]
- Kilic, M.; Kasperczyk, H.; Fulda, S.; Debatin, K.M. Role of hypoxia inducible factor-1α in modulation of apoptosis resistance. Oncogene 2007, 26, 2027–2038. [Google Scholar] [CrossRef]
- Gwak, G.Y.; Yoon, J.H.; Kim, K.M.; Lee, H.S.; Chung, J.W.; Gores, G.J. Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression. J. Hepatol. 2005, 42, 358–364. [Google Scholar] [CrossRef] [PubMed]
- Weinmann, M.; Marini, P.; Jendrossek, V.; Betsch, A.; Goecke, B.; Budach, W.; Belka, C. Influence of hypoxia on TRAIL-induced apoptosis in tumor cells. Int. J. Radiat. Oncol. Biol. Phys. 2004, 58, 386–396. [Google Scholar] [CrossRef] [PubMed]
- Hu, L.; Tang, J.; Huang, X.; Zhang, T.; Feng, X. Hypoxia exposure upregulates MALAT-1 and regulates the transcriptional activity of PTB-associated splicing factor in A549 lung adenocarcinoma cells. Oncol. Lett. 2018, 16, 294–300. [Google Scholar] [CrossRef] [PubMed]
- Koch, S.; Mayer, F.; Honecker, F.; Schittenhelm, M.; Bokemeyer, C. Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro. Br. J. Cancer 2003, 89, 2133–2139. [Google Scholar] [CrossRef] [PubMed]
- Ljungkvist, A.S.; Bussink, J.; Rijken, P.F.; Kaanders, J.H.; van der Kogel, A.J.; Denekamp, J. Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 2002, 54, 215–228. [Google Scholar] [CrossRef]
- Koritzinsky, M.; Rouschop, K.M.A.; van den Beucken, T.; Magagnin, M.G.; Savelkouls, K.; Lambin, P.; Wouters, B.G. Phosphorylation of eIF2α is required for mRNA translation inhibition and survival during moderate hypoxia. Radiother. Oncol. 2007, 83, 353–361. [Google Scholar] [CrossRef]
- Koritzinsky, M.; Levitin, F.; van den Beucken, T.; Rumantir, R.A.; Harding, N.J.; Chu, K.C.; Boutros, P.C.; Braakman, I.; Wouters, B.G. Two phases of disulfide bond formation have differing requirements for oxygen. J. Cell Biol. 2013, 203, 615–627. [Google Scholar] [CrossRef]
- Rouschop, K.M.; van den Beucken, T.; Dubois, L.; Niessen, H.; Bussink, J.; Savelkouls, K.; Keulers, T.; Mujcic, H.; Landuyt, W.; Voncken, J.W.; et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Investig. 2010, 120, 127–141. [Google Scholar] [CrossRef]
- Romero-Ramirez, L.; Cao, H.; Nelson, D.; Hammond, E.; Lee, A.H.; Yoshida, H.; Mori, K.; Glimcher, L.H.; Denko, N.C.; Giaccia, A.J.; et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 2004, 64, 5943–5947. [Google Scholar] [CrossRef]
- Koumenis, C.; Naczki, C.; Koritzinsky, M.; Rastani, S.; Diehl, A.; Sonenberg, N.; Koromilas, A.; Wouters, B.G. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2α. Mol. Cell. Biol. 2002, 22, 7405–7416. [Google Scholar] [CrossRef]
- Blais, J.D.; Filipenko, V.; Bi, M.X.; Harding, H.P.; Ron, D.; Koumenis, C.; Wouters, B.G.; Bell, J.C. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol. Cell. Biol. 2004, 24, 7469–7482. [Google Scholar] [CrossRef] [PubMed]
- Ng, N.; Purshouse, K.; Foskolou, I.P.; Olcina, M.M.; Hammond, E.M. Challenges to DNA replication in hypoxic conditions. FEBS J. 2018, 285, 1563–1571. [Google Scholar] [CrossRef] [PubMed]
- Bencokova, Z.; Kaufmann, M.R.; Pires, I.M.; Lecane, P.S.; Giaccia, A.J.; Hammond, E.M. ATM Activation and Signaling under Hypoxic Conditions. Mol. Cell. Biol. 2009, 29, 526–537. [Google Scholar] [CrossRef] [PubMed]
- Economopoulou, M.; Langer, H.F.; Celeste, A.; Orlova, V.V.; Choi, E.Y.; Ma, M.; Vassilopoulos, A.; Callen, E.; Deng, C.; Bassing, C.H.; et al. Histone H2AX is integral to hypoxia-driven neovascularization. Nat. Med. 2009, 15, 553–558. [Google Scholar] [CrossRef]
- Hammond, E.M.; Dorie, M.J.; Giaccia, A.J. Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res. 2004, 64, 6556–6562. [Google Scholar] [CrossRef]
- Pettersen, E.O.; Lindmo, T. Inhibition of Cell-Cycle Progression by Acute Treatment with Various Degrees of Hypoxia—Modifications Induced by Low Concentrations of Misonidazole Present during Hypoxia. Br. J. Cancer 1983, 48, 809–817. [Google Scholar] [CrossRef]
- Foskolou, I.P.; Jorgensen, C.; Leszczynska, K.B.; Olcina, M.M.; Tarhonskaya, H.; Haisma, B.; D’Angiolella, V.; Myers, W.K.; Domene, C.; Flashman, E.; et al. Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication. Mol. Cell 2017, 66, 206–220. [Google Scholar] [CrossRef]
- Olcina, M.M.; Foskolou, I.P.; Anbalagan, S.; Senra, J.M.; Pires, I.M.; Jiang, Y.Y.; Ryan, A.J.; Hammond, E.M. Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication. Mol. Cell 2013, 52, 758–766. [Google Scholar] [CrossRef]
- Begg, K.; Tavassoli, M. Inside the hypoxic tumour: Reprogramming of the DDR and radioresistance. Cell Death Discov. 2020, 6, 1–15. [Google Scholar] [CrossRef]
- Bindra, R.S.; Schaffer, P.J.; Meng, A.; Woo, J.; Maseide, K.; Roth, M.E.; Lizardi, P.; Hedley, D.W.; Bristow, R.G.; Glazer, P.M. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol. Cell. Biol. 2004, 24, 8504–8518. [Google Scholar] [CrossRef]
- Pires, I.M.; Bencokova, Z.; Milani, M.; Folkes, L.K.; Li, J.L.; Stratford, M.R.; Harris, A.L.; Hammond, E.M. Effects of Acute versus Chronic Hypoxia on DNA Damage Responses and Genomic Instability. Cancer Res. 2010, 70, 925–935. [Google Scholar] [CrossRef] [PubMed]
- Coquelle, A.; Toledo, F.; Stern, S.; Bieth, A.; Debatisse, M. A new role for hypoxia in tumor progression: Induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol. Cell 1998, 2, 259–265. [Google Scholar] [CrossRef]
- Reynolds, T.Y.; Rockwell, S.; Glazer, P.M. Genetic instability induced by the tumor microenvironment. Cancer Res. 1996, 56, 5754–5757. [Google Scholar] [PubMed]
- Rofstad, E.K.; Johnsen, N.M.; Lyng, H. Hypoxia-induced tetraploidisation of a diploid human melanoma cell line in vitro. Br. J. Cancer 1996, 27, S136–S139. [Google Scholar]
- Rofstad, E.K.; Danielsen, T. Hypoxia-induced metastasis of human melanoma cells: Involvement of vascular endothelial growth factor-mediated angiogenesis. Br. J. Cancer 1999, 80, 1697–1707. [Google Scholar] [CrossRef] [PubMed]
- Young, S.D.; Hill, R.P. Effects of reoxygenation on cells from hypoxic regions of solid tumors: Anticancer drug sensitivity and metastatic potential. J. Natl. Cancer Inst. 1990, 82, 371–380. [Google Scholar] [CrossRef]
- Young, S.D.; Marshall, R.S.; Hill, R.P. Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc. Natl. Acad. Sci. USA 1988, 85, 9533–9537. [Google Scholar] [CrossRef]
- Kumareswaran, R.; Ludkovski, O.; Meng, A.; Sykes, J.; Pintilie, M.; Bristow, R.G. Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability. J. Cell Sci. 2012, 125, 189–199. [Google Scholar] [CrossRef]
- Tan, Q.; Wang, M.; Yu, M.; Zhang, J.; Bristow, R.G.; Hill, R.P.; Tannock, I.F. Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors. Neoplasia 2016, 18, 347–355. [Google Scholar] [CrossRef]
- Graeber, T.G.; Osmanian, C.; Jacks, T.; Housman, D.E.; Koch, C.J.; Lowe, S.W.; Giaccia, A.J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996, 379, 88–91. [Google Scholar] [CrossRef]
- Amellem, O.; Stokke, T.; Sandvik, J.A.; Smedshammer, L.; Pettersen, E.O. Hypoxia-induced apoptosis in human cells with normal p53 status and function, without any alteration in the nuclear protein level. Exp. Cell Res. 1997, 232, 361–370. [Google Scholar] [CrossRef] [PubMed]
- Bellot, G.; Garcia-Medina, R.; Gounon, P.; Chiche, J.; Roux, D.; Pouyssegur, J.; Mazure, N.M. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell. Biol. 2009, 29, 2570–2581. [Google Scholar] [CrossRef] [PubMed]
- Noman, M.Z.; Janji, B.; Kaminska, B.; Van Moer, K.; Pierson, S.; Przanowski, P.; Buart, S.; Berchem, G.; Romero, P.; Mami-Chouaib, F.; et al. Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression. Cancer Res. 2011, 71, 5976–5986. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Bosch-Marce, M.; Shimoda, L.A.; Tan, Y.S.; Baek, J.H.; Wesley, J.B.; Gonzalez, F.J.; Semenza, G.L. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 2008, 283, 10892–10903. [Google Scholar] [CrossRef]
- Eisinger-Mathason, T.S.; Zhang, M.; Qiu, Q.; Skuli, N.; Nakazawa, M.S.; Karakasheva, T.; Mucaj, V.; Shay, J.E.; Stangenberg, L.; Sadri, N.; et al. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov. 2013, 3, 1190–1205. [Google Scholar] [CrossRef]
- Wei, L.; Song, X.R.; Sun, J.J.; Wang, X.W.; Xie, L.; Lv, L.Y. Lysyl oxidase may play a critical role in hypoxia-induced NSCLC cells invasion and migration. Cancer Biother. Radiopharm. 2012, 27, 672–677. [Google Scholar] [CrossRef]
- Graham, C.H.; Forsdike, J.; Fitzgerald, C.J.; Macdonald-Goodfellow, S. Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int. J. Cancer 1999, 80, 617–623. [Google Scholar] [CrossRef]
- Yang, X.; Li, S.; Li, W.; Chen, J.; Xiao, X.; Wang, Y.; Yan, G.; Chen, L. Inactivation of lysyl oxidase by β-aminopropionitrile inhibits hypoxia-induced invasion and migration of cervical cancer cells. Oncol. Rep. 2013, 29, 541–548. [Google Scholar] [CrossRef]
- Guo, M.; Cai, C.; Zhao, G.; Qiu, X.; Zhao, H.; Ma, Q.; Tian, L.; Li, X.; Hu, Y.; Liao, B.; et al. Hypoxia promotes migration and induces CXCR4 expression via HIF-1α activation in human osteosarcoma. PLoS ONE 2014, 9, e90518. [Google Scholar] [CrossRef]
- Lester, R.D.; Jo, M.; Montel, V.; Takimoto, S.; Gonias, S.L. uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J. Cell Biol. 2007, 178, 425–436. [Google Scholar] [CrossRef]
- Munoz-Najar, U.M.; Neurath, K.M.; Vumbaca, F.; Claffey, K.P. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene 2006, 25, 2379–2392. [Google Scholar] [CrossRef] [PubMed]
- Canning, M.T.; Postovit, L.M.; Clarke, S.H.; Graham, C.H. Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells. Exp. Cell Res. 2001, 267, 88–94. [Google Scholar] [CrossRef] [PubMed]
- Lewis, D.M.; Park, K.M.; Tang, V.; Xu, Y.; Pak, K.; Eisinger-Mathason, T.S.; Simon, M.C.; Gerecht, S. Intratumoral oxygen gradients mediate sarcoma cell invasion. Proc. Natl. Acad. Sci. USA 2016, 113, 9292–9297. [Google Scholar] [CrossRef] [PubMed]
- de Palma, M.; Biziato, D.; Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 2017, 17, 457–474. [Google Scholar] [CrossRef]
- Schito, L.; Rey, S. Hypoxia: Turning vessels into vassals of cancer immunotolerance. Cancer Lett. 2020, 487, 74–84. [Google Scholar] [CrossRef]
- Klomp, J.; Hyun, J.; Klomp, J.E.; Pajcini, K.; Rehman, J.; Malik, A.B. Comprehensive transcriptomic profiling reveals SOX7 as an early regulator of angiogenesis in hypoxic human endothelial cells. J. Biol. Chem. 2020, 295, 4796–4808. [Google Scholar] [CrossRef]
- Staples, K.J.; Sotoodehnejadnematalahi, F.; Pearson, H.; Frankenberger, M.; Francescut, L.; Ziegler-Heitbrock, L.; Burke, B. Monocyte-derived macrophages matured under prolonged hypoxia transcriptionally up-regulate HIF-1α mRNA. Immunobiology 2011, 216, 832–839. [Google Scholar] [CrossRef]
- Chiarotto, J.A.; Hill, R.P. A quantitative analysis of the reduction in oxygen levels required to induce up-regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cancer cell lines. Br. J. Cancer 1999, 80, 1518–1524. [Google Scholar] [CrossRef][Green Version]
- Triner, D.; Shah, Y.M. Hypoxia-inducible factors: A central link between inflammation and cancer. J. Clin. Investig. 2016, 126, 3689–3698. [Google Scholar] [CrossRef]
- Vuillefroy de Silly, R.; Dietrich, P.Y.; Walker, P.R. Hypoxia and antitumor CD8(+) T cells: An incompatible alliance? Oncoimmunology 2016, 5, e1232236. [Google Scholar] [CrossRef]
- D’Ignazio, L.; Batie, M.; Rocha, S. Hypoxia and Inflammation in Cancer, Focus on HIF and NF-κB. Biomedicines 2017, 5, 21. [Google Scholar] [CrossRef] [PubMed]
- Chiu, D.K.; Tse, A.P.; Xu, I.M.; Di Cui, J.; Lai, R.K.; Li, L.L.; Koh, H.Y.; Tsang, F.H.; Wei, L.L.; Wong, C.M.; et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat. Commun. 2017, 8, 517. [Google Scholar] [CrossRef] [PubMed]
- Van Overmeire, E.; Laoui, D.; Keirsse, J.; Van Ginderachter, J.A. Hypoxia and tumor-associated macrophages: A deadly alliance in support of tumor progression. Oncoimmunology 2014, 3, e27561. [Google Scholar] [CrossRef] [PubMed]
- Murdoch, C.; Giannoudis, A.; Lewis, C.E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 2004, 104, 2224–2234. [Google Scholar] [CrossRef] [PubMed]
- Facciabene, A.; Peng, X.; Hagemann, I.S.; Balint, K.; Barchetti, A.; Wang, L.P.; Gimotty, P.A.; Gilks, C.B.; Lal, P.; Zhang, L.; et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011, 475, 226–230. [Google Scholar] [CrossRef]
- Henze, A.-T.; Mazzone, M. The impact of hypoxia on tumor-associated macrophages. J. Clin. Investig. 2016, 126, 3672–3679. [Google Scholar] [CrossRef]
- Lewis, C.E.; Pollard, J.W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006, 66, 605–612. [Google Scholar] [CrossRef]
- Doedens, A.L.; Stockmann, C.; Rubinstein, M.P.; Liao, D.; Zhang, N.; DeNardo, D.G.; Coussens, L.M.; Karin, M.; Goldrath, A.W.; Johnson, R.S. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res. 2010, 70, 7465–7475. [Google Scholar] [CrossRef]
- Hatfield, S.M.; Kjaergaard, J.; Lukashev, D.; Schreiber, T.H.; Belikoff, B.; Abbott, R.; Sethumadhavan, S.; Philbrook, P.; Ko, K.; Cannici, R.; et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 2015, 7, 277ra230. [Google Scholar] [CrossRef]
- Jayaprakash, P.; Ai, M.; Liu, A.; Budhani, P.; Bartkowiak, T.; Sheng, J.; Ager, C.; Nicholas, C.; Jaiswal, A.R.; Sun, Y.; et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J. Clin. Investig. 2018, 128, 5137–5149. [Google Scholar] [CrossRef]
- Murthy, A.; Gerber, S.A.; Koch, C.J.; Lord, E.M. Intratumoral Hypoxia Reduces IFN-γ-Mediated Immunity and MHC Class I Induction in a Preclinical Tumor Model. Immunohorizons 2019, 3, 149–160. [Google Scholar] [CrossRef] [PubMed]
- Scharping, N.E.; Menk, A.V.; Whetstone, R.D.; Zeng, X.; Delgoffe, G.M. Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol. Res. 2017, 5, 9–16. [Google Scholar] [CrossRef] [PubMed]
- Vuillefroy de Silly, R.; Ducimetiere, L.; Yacoub Maroun, C.; Dietrich, P.Y.; Derouazi, M.; Walker, P.R. Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. Eur. J. Immunol. 2015, 45, 2263–2275. [Google Scholar] [CrossRef] [PubMed]
- Barsoum, I.B.; Smallwood, C.A.; Siemens, D.R.; Graham, C.H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014, 74, 665–674. [Google Scholar] [CrossRef] [PubMed]
- Niemeijer, A.L.; Hoekstra, O.S.; Smit, E.F.; de Langen, A.J. Imaging Responses to Immunotherapy with Novel PET Tracers. J. Nucl. Med. 2020, 61, 641–642. [Google Scholar] [CrossRef]
- Iversen, A.B.; Horsman, M.R.; Jakobsen, S.; Jensen, J.B.; Garm, C.; Jessen, N.; Breining, P.; Frokiaer, J.; Busk, M. Results from C-11-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly. Sci. Rep. 2017, 7. [Google Scholar] [CrossRef]
- Halle, C.; Andersen, E.; Lando, M.; Aarnes, E.K.; Hasvold, G.; Holden, M.; Syljuasen, R.G.; Sundfor, K.; Kristensen, G.B.; Holm, R.; et al. Hypoxia-induced gene expression in chemoradioresistant cervical cancer revealed by dynamic contrast-enhanced MRI. Cancer Res. 2012, 72, 5285–5295. [Google Scholar] [CrossRef]
- Welz, S.; Monnich, D.; Pfannenberg, C.; Nikolaou, K.; Reimold, M.; La Fougere, C.; Reischl, G.; Mauz, P.S.; Paulsen, F.; Alber, M.; et al. Prognostic value of dynamic hypoxia PET in head and neck cancer: Results from a planned interim analysis of a randomized phase II hypoxia-image guided dose escalation trial. Radiother. Oncol. 2017, 124, 526–532. [Google Scholar] [CrossRef]
- Gregoire, V.; Guckenberger, M.; Haustermans, K.; Lagendijk, J.J.W.; Menard, C.; Potter, R.; Slotman, B.J.; Tanderup, K.; Thorwarth, D.; van Herk, M.; et al. Image guidance in radiation therapy for better cure of cancer. Mol. Oncol. 2020, 14, 1470–1491. [Google Scholar] [CrossRef]
- Vishwanath, K.; Klein, D.; Chang, K.; Schroeder, T.; Dewhirst, M.W.; Ramanujam, N. Quantitative optical spectroscopy can identify long-term local tumor control in irradiated murine head and neck xenografts. J. Biomed. Opt. 2009, 14. [Google Scholar] [CrossRef]
- Zips, D.; Zophel, K.; Abolmaali, N.; Perrin, R.; Abramyuk, A.; Haase, R.; Appold, S.; Steinbach, J.; Kotzerke, J.; Baumann, M. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother. Oncol. 2012, 105, 21–28. [Google Scholar] [CrossRef] [PubMed]
- Vitti, E.T.; Parsons, J.L. The Radiobiological Effects of Proton Beam Therapy: Impact on DNA Damage and Repair. Cancers 2019, 11, 946. [Google Scholar] [CrossRef] [PubMed]
- Wilson, J.D.; Hammond, E.M.; Higgins, G.S.; Petersson, K. Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool’s Gold? Front. Oncol. 2020, 9, 1563. [Google Scholar] [CrossRef] [PubMed]
- Petersson, K.; Adrian, G.; Butterworth, K.; McMahon, S.J. A Quantitative Analysis of the Role of Oxygen Tension in FLASH Radiation Therapy. Int. J. Radiat. Oncol. 2020, 107, 539–547. [Google Scholar] [CrossRef]
- Hunter, F.W.; Wouters, B.G.; Wilson, W.R. Hypoxia-activated prodrugs: Paths forward in the era of personalised medicine. Br. J. Cancer 2016, 114, 1071–1077. [Google Scholar] [CrossRef]
- Overgaard, J.; Hansen, H.S.; Overgaard, M.; Bastholt, L.; Berthelsen, A.; Specht, L.; Lindelov, B.; Jorgensen, K. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma, results of the Danish Head and Neck Cancer Study (DAHANCA) protocol 5-85. Radiother. Oncol. 1998, 46, 135–146. [Google Scholar] [CrossRef]
- Minn, H.; Clavo, A.C.; Fisher, S.J.; Wahl, R.L. Effect of nitroimidazole sensitizers on in vitro glycolytic metabolism of hypoxic squamous cell carcinoma. Acta Oncol. 2000, 39, 199–205. [Google Scholar]
- Hicks, K.O.; Myint, H.; Patterson, A.V.; Pruijn, F.B.; Siim, B.G.; Patel, K.; Wilson, W.R. Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: Comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int. J. Radiat. Oncol. 2007, 69, 560–571. [Google Scholar] [CrossRef]
- Meng, F.Y.; Evans, J.W.; Bhupathi, D.; Banica, M.; Lan, L.; Lorente, G.; Duan, J.X.; Cai, X.H.; Mowday, A.M.; Guise, C.P.; et al. Molecular and Cellular Pharmacology of the Hypoxia-Activated Prodrug TH-302. Mol. Cancer Ther. 2012, 11, 740–751. [Google Scholar] [CrossRef]
- Ashton, T.M.; McKenna, W.G.; Kunz-Schughart, L.A.; Higgins, G.S. Oxidative Phosphorylation as an Emerging Target in Cancer Therapy. Clin. Cancer Res. 2018, 24, 2482–2490. [Google Scholar] [CrossRef]
- Wang, S.; Lin, Y.; Xiong, X.; Wang, L.; Guo, Y.; Chen, Y.; Chen, S.; Wang, G.; Lin, P.; Chen, H.; et al. Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial. Clin. Cancer Res. 2020, 26, 4921–4932. [Google Scholar] [CrossRef] [PubMed]
- Gerber, S.A.; Lim, J.Y.H.; Connolly, K.A.; Sedlacek, A.L.; Barlow, M.L.; Murphy, S.P.; Egilmez, N.K.; Lord, E.M. Radio-responsive tumors exhibit greater intratumoral immune activity than nonresponsive tumors. Int. J. Cancer 2014, 134, 2383–2392. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Tubin, S.; Popper, H.H.; Brcic, L. Novel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): Improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects. Radiat. Oncol. 2019, 14. [Google Scholar] [CrossRef] [PubMed]
- Tubin, S.; Ashdown, M.; Jeremic, B. Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment. Radiat. Oncol. 2019, 14. [Google Scholar] [CrossRef] [PubMed]
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Hompland, T.; Fjeldbo, C.S.; Lyng, H. Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter. Cancers 2021, 13, 499. https://doi.org/10.3390/cancers13030499
Hompland T, Fjeldbo CS, Lyng H. Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter. Cancers. 2021; 13(3):499. https://doi.org/10.3390/cancers13030499
Chicago/Turabian StyleHompland, Tord, Christina Sæten Fjeldbo, and Heidi Lyng. 2021. "Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter" Cancers 13, no. 3: 499. https://doi.org/10.3390/cancers13030499
APA StyleHompland, T., Fjeldbo, C. S., & Lyng, H. (2021). Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter. Cancers, 13(3), 499. https://doi.org/10.3390/cancers13030499