Tumour microenvironments harbour multiple microdomains whereby cells experience limited (and highly variable) access to oxygen and nutrients.
Oxygen and nutrient availability affect tumour evolution via altered metabolism, blood vessel recruitment, inflammatory cell infiltration and metastasis.
Although much of hypoxia research has previously focused on hypoxia-inducible factor (HIF) transcriptional regulators, multiple additional O2-sensing mechanisms are at play, including those regulated by mTOR complex 1 (mTORC1), endoplasmic reticulum stress responses, autophagy and numerous oxygen-consuming metabolic pathways.
The HIFs, as central regulators of metabolic adaptations in hypoxic tumours, significantly influence intracellular metabolism but are also in turn governed by changes in metabolite accumulation.
The human genome encodes up to 70 2-oxoglutarate-dependent dioxygenases that probably contribute to tumour phenotypes at the biosynthetic, metabolic, genetic and epigenetic levels.
Oxygen availability, along with the abundance of nutrients (such as glucose, glutamine, lipids and albumin), fluctuates significantly during tumour evolution and the recruitment of blood vessels, leukocytes and reactive fibroblasts to complex tumour microenvironments. As such, hypoxia and concomitant nutrient scarcity affect large gene expression programmes, signalling pathways, diverse metabolic reactions and various stress responses. This Review summarizes our current understanding of how these adaptations are integrated in hypoxic tumour cells and their role in disease progression.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Tumor microenvironment: barrier or opportunity towards effective cancer therapy
Journal of Biomedical Science Open Access 17 October 2022
Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation
Cell Death & Disease Open Access 27 July 2022
Hypoxia signaling in human health and diseases: implications and prospects for therapeutics
Signal Transduction and Targeted Therapy Open Access 07 July 2022
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Lee, K. E. & Simon, M. C. SnapShot: hypoxia-inducible factors. Cell 163, 1288 (2015).
Qiu, B. & Simon, M. C. Oncogenes strike a balance between cellular growth and homeostasis. Semin. Cell Dev. Biol. 43, 3–10 (2015).
Ratcliffe, P. J. Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J. Physiol. 591, 2027–2042 (2013).
Brizel, D. M. et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56, 941–943 (1996).
Hockel, M. et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother. Oncol. 26, 45–50 (1993). This paper was among the first to directly measure tumour oxygenation in 15 patients undergoing radiotherapy treatment, and demonstrated that pO 2 can be an independent prognostic factor influencing survival in advanced-stage cancer of the uterine cervix.
Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).
Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).
Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).
Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 12, 149–162 (1998).
Gordan, J. D., Thompson, C. B. & Simon, M. C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113 (2007).
Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006). References 11 and 12 demonstrated that the HIF1α target PDK1, which inactivates PDH, results in a hypoxia-induced metabolic switch that shunts glucose metabolites away from the mitochondria to glycolysis, to maintain ATP production and prevent toxic ROS build-up.
Guzy, R. D. et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 1, 401–408 (2005).
Mansfield, K. D. et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab. 1, 393–399 (2005).
Chandel, N. S. et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275, 25130–25138 (2000).
Lee, G. et al. Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation. Sci. Rep. 6, 18928 (2016).
Dupuy, F. et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 22, 577–589 (2015).
Doherty, J. R. & Cleveland, J. L. Targeting lactate metabolism for cancer therapeutics. J. Clin. Invest. 123, 3685–3692 (2013).
Fukuda, R. et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122 (2007).
Tello, D. et al. Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 14, 768–779 (2011).
Hervouet, E. et al. A new role for the von Hippel–Lindau tumor suppressor protein: stimulation of mitochondrial oxidative phosphorylation complex biogenesis. Carcinogenesis 26, 531–539 (2005).
Zhang, H. et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11, 407–420 (2007).
Walter, K. M. et al. Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy. Cell Metab. 20, 882–897 (2014).
Rao, X. et al. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth. Nat. Commun. 6, 8468 (2015).
Yi, W. et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337, 975–980 (2012).
Cheung, E. C., Ludwig, R. L. & Vousden, K. H. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc. Natl Acad. Sci. USA 109, 20491–20496 (2012).
Favaro, E. et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 16, 751–764 (2012).
Luo, W. et al. Pyruvate kinase M2 Is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744 (2011).
Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 21, 65–80 (2015).
Yang, W. et al. EGFR-induced and PKCepsilon monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol. Cell 48, 771–784 (2012).
Jiang, Y. et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol. Cell 53, 75–87 (2014).
Jiang, Y. et al. PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat. Commun. 5, 5566 (2014).
Israelsen, W. J. et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397–409 (2013).
Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014). This paper describes a prominent metabolic enzyme that has both catalytic and structural roles in regulating both intracellular metabolism and nuclear transcription factor activity; other enzymes such as PKM2 and argininosuccinate synthase 1 (ASS1) represent additional examples of enzymes with key adaptor protein functions beyond their traditional enzymatic functions.
Pollard, P. J., Wortham, N. C. & Tomlinson, I. P. The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase. Ann. Med. 35, 632–639 (2003).
Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002).
Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).
Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005). References 37 and 38 describe how TCA cycle intermediates such as succinate and fumarate, represent a mitochondrion to cytosol signalling pathway that links mitochondrial dysfunction downstream of mutations in enzymes, such as SDH and FH, to inhibit the PHD-mediated turnover of HIF1α.
Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007).
Masson, N., William, C., Maxwell, P. H., Pugh, C. W. & Ratcliffe, P. J. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 20, 5197–5206 (2001).
Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).
Markolovic, S., Wilkins, S. E. & Schofield, C. J. Protein hydroxylation catalyzed by 2-oxoglutarate-dependent oxygenases. J. Biol. Chem. 290, 20712–20722 (2015).
Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010). Ward et al . demonstrate that a shared feature of cancer-associated IDH mutations is the production of extremely high levels of the oncometabolite 2HG.
Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012).
Tarhonskaya, H. et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat. Commun. 5, 3423 (2014).
Nytko, K. J. et al. Vitamin C is dispensable for oxygen sensing in vivo. Blood 117, 5485–5493 (2011).
Knowles, H. J., Raval, R. R., Harris, A. L. & Ratcliffe, P. J. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res. 63, 1764–1768 (2003).
Knowles, H. J., Mole, D. R., Ratcliffe, P. J. & Harris, A. L. Normoxic stabilization of hypoxia-inducible factor-1alpha by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Cancer Res. 66, 2600–2607 CAN-05-2351 (2006).
Kuiper, C., Dachs, G. U., Currie, M. J. & Vissers, M. C. Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic. Biol. Med. 69, 308–317 (2014).
Kuiper, C. et al. Increased tumor ascorbate is associated with extended disease-free survival and decreased hypoxia-inducible factor-1 activation in human colorectal cancer. Front. Oncol. 4, 10 (2014).
Ramakrishnan, S. K. & Shah, Y. M. Role of intestinal HIF-2α in health and disease. Annu. Rev. Physiol. 78, 301–325 (2016).
Mastrogiannaki, M., Matak, P. & Peyssonnaux, C. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 122, 885–892 (2013).
Zimmer, M. et al. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol. Cell 32, 838–848 (2008).
Gruber, M. et al. Acute postnatal ablation of Hif-2α results in anemia. Proc. Natl Acad. Sci. USA 104, 2301–2306 (2007).
Rankin, E. B. et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J. Clin. Invest. 117, 1068–1077 (2007).
Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-keto-glutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).
Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).
Mullen, A. R. et al. Oxidation of α-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7, 1679–1690 (2014). References 58–60 demonstrate that hypoxia and mutations in key TCA cycle enzymes result in reductive carboxylation of 2OG, which can support lipid homeostasis, especially downstream of glutamine catabolism.
Sun, R. C. & Denko, N. C. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 19, 285–292 (2014).
Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).
Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).
Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014).
Ackerman, D. & Simon, M. C. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 24, 472–478 (2014).
Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).
Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).
Zaidi, N. et al. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog. Lipid Res. 52, 585–589 (2013).
Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).
Kuemmerle, N. B. et al. Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol. Cancer Ther. 10, 427–436 MCT-10-0802 (2011).
Young, R. M. et al. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 27, 1115–1131 (2013). This was one of the first papers to show that a fundamental biosynthetic reaction, that is, fatty acid desaturation, can be inhibited by pO 2 levels typical of hypoxic microdomains detected in solid tumours.
Wang, D., Wei, Y. & Pagliassotti, M. J. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147, 943–951 (2006).
Kamphorst, J. J. et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl Acad. Sci. USA 110, 8882–8887 (2013).
Qiu, B. et al. HIF-2α dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma. Cancer Discov. 5, 652–657 (2015).
Bensaad, K. et al. Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 9, 349–365 (2014).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011).
Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013). References 76–78 convincingly demonstrate that the oncometabolite 2HG affects the epigenome via histone methylation status.
Intlekofer, A. M. et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015).
Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015).
Harris, A. L. A. New hydroxy metabolite of 2-oxoglutarate regulates metabolism in hypoxia. Cell Metab. 22, 198–200 (2015).
Shim, E. H. et al. L-2-hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014).
Lee, D. C. et al. A lactate-induced response to hypoxia. Cell 161, 595–609 (2015).
Loenarz, C. & Schofield, C. J. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat. Chem. Biol. 4, 152–156 (2008).
Hirsila, M. et al. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 19, 1308–1310 (2005).
Koivunen, P., Hirsila, M., Kivirikko, K. I. & Myllyharju, J. The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J. Biol. Chem. 281, 28712–28720 (2006).
Hewitson, K. S. et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J. Biol. Chem. 282, 3293–3301 (2007).
Pan, Y. et al. Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol. Cell. Biol. 27, 912–925 (2007).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).
Deberardinis, R. J., Sayed, N., Ditsworth, D. & Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18, 54–61 (2008).
Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521–531 (2006).
Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R. & Kaelin, W. G. Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147–158 (2003).
Faubert, B. et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α. Proc. Natl Acad. Sci. USA 111, 2554–2559 (2014).
Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).
Reiling, J. H. & Hafen, E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18, 2879–2892 (2004).
Corradetti, M. N., Inoki, K. & Guan, K. L. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J. Biol. Chem. 280, 9769–9772 (2005).
Miyazaki, M. & Esser, K. A. REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch. Am. J. Physiol. Cell Physiol. 296, C583–592 (2009).
Elorza, A. et al. HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol. Cell 48, 681–691 (2012).
Keith, B., Johnson, R. S. & Simon, M. C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9–22 (2012).
Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008).
Gulati, P. et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab. 7, 456–465 (2008).
Chen, S. et al. CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death. J. Neurochem. 119, 1108–1118 (2011).
Nakazawa, M. S. et al. Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth. Nat. Commun. 7, 10539 (2016).
Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nat. Rev. Cancer 7, 961–967 (2007).
Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
Morselli, E. et al. Anti- and pro-tumor functions of autophagy. Biochim. Biophys. Acta 1793, 1524–1532 (2009).
Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
Rouschop, K. M. et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Invest. 120, 127–141 (2010).
Maiuri, M. C., Zalckvar, E., Kimchi, A. & Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752 (2007).
Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).
Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).
Gupta, A. et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc. Natl Acad. Sci. USA 107, 14333–14338 (2010).
Yamamoto, A. et al. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 23, 33–42 (1998).
Bellot, G. et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell. Biol. 29, 2570–2581 (2009).
Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nat. Rev. Cancer 8, 967–975 (2008).
Semenza, G. L. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr. Pharm. Des. 15, 3839–3843 (2009).
Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9, 271–276 (2013).
Wu, D., Potluri, N., Lu, J., Kim, Y. & Rastinejad, F. Structural integration in hypoxia-inducible factors. Nature 524, 303–308 (2015). This paper describes crystal structures for each of the HIF1α–ARNT and HIF2α–ARNT heterodimers in states that include bound small molecules and HRE DNA.
Pourmorteza, M., Rahman, Z. U. & Young, M. Evofosfamide, a new horizon in the treatment of pancreatic cancer. Anticancer Drugs 27, 723–725 (2016).
Lohse, I. et al. Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302. Oncotarget http://dx.doi.org/10.18632/oncotarget.9654 (2016).
Zhang, X. et al. MR imaging biomarkers to monitor early response to hypoxia-activated prodrug TH-302 in pancreatic cancer xenografts. PLoS ONE 11, e0155289 (2016).
The authors would like to specifically thank F. Tucker for her assistance in preparing the manuscript. M.S.N.'s research is supported by the US National Cancer Institute (NCI) R01 CA158301; B.K. and M.C.S acknowledge support from NCI P01 CA104838.
The authors declare no competing financial interests.
- Ischaemic conditions
Tissue environment in which cells are limited for oxygen and other blood-borne nutrients (such as glucose, glutamine, lipids and albumin) simultaneously, as opposed to being merely O2 deprived or hypoxic.
Central carbon metabolic pathway in which glucose is catabolized to lactate and/or pyruvate.
- Redox stress
Pathological setting in which cells and tissues experience an imbalance in oxidant versus antioxidant agents.
- Reactive oxygen species
(ROS). Oxygen-containing molecules harbouring an additional unpaired electron; for example, H2O2, OH− and O2−.
A specialized form of autophagy devoted to breakdown of mitochondria in response to certain stimuli.
The reverse pathway in central carbon metabolism (relative to glycolysis) in which glucose is generated from precursors, and maintained as free glucose or converted into storage depots such as glycogen.
An intracellular process whereby tricarboxylic acid (TCA) cycle intermediates are replenished when they become limiting; for example, when entry of glucose-derived carbons is insufficient to maintain the mitochondrial TCA cycle, glutamine-derived carbons can replenish the pathway, maintaining homeostasis.
- Phytanic acid
3,7,11,15-tetramethylhexadecanoic acid, a branched-chain fatty acid that humans obtain via consumption of, for example, diary products, beef and fish.
Rights and permissions
About this article
Cite this article
Nakazawa, M., Keith, B. & Simon, M. Oxygen availability and metabolic adaptations. Nat Rev Cancer 16, 663–673 (2016). https://doi.org/10.1038/nrc.2016.84
This article is cited by
FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway
Stem Cell Research & Therapy (2022)
Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation
Journal of Nanobiotechnology (2022)
CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2
Molecular Cancer (2022)
Tumor microenvironment: barrier or opportunity towards effective cancer therapy
Journal of Biomedical Science (2022)
Hypoxia signaling in human health and diseases: implications and prospects for therapeutics
Signal Transduction and Targeted Therapy (2022)