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Hypoxia and Metabolism in Metastasis

  • Tong Zhang
  • Caixia Suo
  • Chenyang Zheng
  • Huafeng ZhangEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1136)

Abstract

The hypoxic microenvironment is one of the major features of solid tumors, which regulates cell malignancy in multiple ways. As a response to hypoxia, a large number of target genes involved in cell growth, metabolism, metastasis and immunity are activated in cancer cells. Hypoxia-inducible factor 1 (HIF-1), as a heterodimeric DNA-binding complex, is comprised of a constitutively expressed HIF-1β subunit and an oxygen sensitive HIF-1α subunit, thus, adapts to decreased oxygen availability as a transcriptional factor. HIF-1 regulates many genes involved in tumorigenesis. Here, we focus on cancer cell metabolism and metastasis regulated by hypoxia.

Keywords

Hypoxia HIF1 Glycolysis Glycogen synthesis Lipid metabolism Metastasis EMT Metastatic niche Mitochondria Metabolic enzymes 

Notes

Acknowledgments

This work was supported in part by grants from the National Natural Science Foundation of China (81525022), the strategic priority research program(Pilot study)of the Chinese Academy of Sciences (XDPB10), and the major innovative program of development foundation of Hefei center for physical science and technology (2017FXZY004).

References

  1. 1.
    Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33:207–214CrossRefGoogle Scholar
  2. 2.
    Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2:758–770CrossRefGoogle Scholar
  3. 3.
    Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, Steers G, Turley H, Li JL, Gunther UL et al (2012) Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab 16:751–764CrossRefGoogle Scholar
  4. 4.
    Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185CrossRefGoogle Scholar
  5. 5.
    Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11:407–420CrossRefGoogle Scholar
  6. 6.
    Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL (2007) HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129:111–122CrossRefGoogle Scholar
  7. 7.
    Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29:2570–2581CrossRefGoogle Scholar
  8. 8.
    Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903CrossRefGoogle Scholar
  9. 9.
    Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordonez A, Corral-Escariz M, Soro I, Lopez-Bernardo E, Perales-Clemente E et al (2011) Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. Cell Metab 14:768–779CrossRefGoogle Scholar
  10. 10.
    Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10:273–284CrossRefGoogle Scholar
  11. 11.
    Bensaad K et al (2014) Fatty acid uptake and lipid storageinduced by HIF-1a contribute to cell growth and survival afterhypoxia-reoxygenation. Cell Rep 9:349–365CrossRefGoogle Scholar
  12. 12.
    Sun RC, Denko NC (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285–292CrossRefGoogle Scholar
  13. 13.
    Huang, Li T, Li X, Zhang L, Sun L, He X, Zhong X, Jia D, Song L, Semenza GL et al (2014) HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 8:1930–1942CrossRefGoogle Scholar
  14. 14.
    Samanta D, Park Y, Andrabi SA, Shelton LM, Gilkes DM, Semenza GL (2016) PHGDH expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis. Cancer Res 76:4430–4442CrossRefGoogle Scholar
  15. 15.
    Ye J, Fan J, Venneti S, Wan YW, Pawel BR, Zhang J, Finley LW, Lu C, Lindsten T, Cross JR et al (2014) Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov 4:1406–1417CrossRefGoogle Scholar
  16. 16.
    Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC et al (2015) Phosphoenolpyruvate Is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–1228CrossRefGoogle Scholar
  17. 17.
    Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K et al (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:657–671CrossRefGoogle Scholar
  18. 18.
    Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563CrossRefGoogle Scholar
  19. 19.
    Lyssiotis CA, Kimmelman AC (2017) Metabolic interactions in the tumor microenvironment. Trends Cell Biol 27:863–875CrossRefGoogle Scholar
  20. 20.
    Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331:1559–1564CrossRefGoogle Scholar
  21. 21.
    Jiang J, Tang Y-l, Liang X-h (2014) EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther 11:714–723CrossRefGoogle Scholar
  22. 22.
    Hugo HJ, Pereira L, Suryadinata R, Drabsch Y, Gonda TJ, Gunasinghe NP, Pinto C, Soo ET, van Denderen BJ, Hill P et al (2013) Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-to-mesenchymal transition of breast cancer cells. Breast Cancer Res 15:R113CrossRefGoogle Scholar
  23. 23.
    Munoz-Najar UM, Neurath KM, Vumbaca F, Claffey KP (2006) Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene 25:2379–2392CrossRefGoogle Scholar
  24. 24.
    Petrella BL, Lohi J, Brinckerhoff CE (2005) Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel-Lindau renal cell carcinoma. Oncogene 24:1043–1052CrossRefGoogle Scholar
  25. 25.
    Graham CH, Forsdike J, Fitzgerald CJ, Macdonald-Goodfellow S (1999) Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int J Cancer 80:617–623CrossRefGoogle Scholar
  26. 26.
    Gilkes DM, Bajpai S, Chaturvedi P, Wirtz D, Semenza GL (2013) Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem 288:10819–10829CrossRefGoogle Scholar
  27. 27.
    Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr et al (2012) HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 31:1757–1770CrossRefGoogle Scholar
  28. 28.
    Jin F, Brockmeier U, Otterbach F, Metzen E (2012) New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required for tumor cell intravasation. Mol Cancer Res 10:1021–1031CrossRefGoogle Scholar
  29. 29.
    Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226CrossRefGoogle Scholar
  30. 30.
    Wong CC, Gilkes DM, Zhang H, Chen J, Wei H, Chaturvedi P, Fraley SI, Wong CM, Khoo US, Ng IO et al (2011) Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA 108:16369–16374CrossRefGoogle Scholar
  31. 31.
    Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146CrossRefGoogle Scholar
  32. 32.
    Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, Morgelin M, Bourseau-Guilmain E, Bengzon J, Belting M (2013) Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci USA 110:7312–7317CrossRefGoogle Scholar
  33. 33.
    Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL (2014) Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci USA 111:E3234–E3242CrossRefGoogle Scholar
  34. 34.
    Loo JM, Scherl A, Nguyen A, Man FY, Weinberg E, Zeng Z, Saltz L, Paty PB, Tavazoie SF (2015) Extracellular metabolic energetics can promote cancer progression. Cell 160:393–406CrossRefGoogle Scholar
  35. 35.
    Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS et al (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503CrossRefGoogle Scholar
  36. 36.
    Gharpure KM, Pradeep S, Sans M, Rupaimoole R, Ivan C, Wu SY, Bayraktar E, Nagaraja AS, Mangala LS, Zhang X et al (2018) FABP4 as a key determinant of metastatic potential of ovarian cancer. Nat Commun 9:2923CrossRefGoogle Scholar
  37. 37.
    Lin CC, Cheng TL, Tsai WH, Tsai HJ, Hu KH, Chang HC, Yeh CW, Chen YC, Liao CC, Chang WT (2012) Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy. Sci Rep 2:785CrossRefGoogle Scholar
  38. 38.
    Dupuy F, Tabaries S, Andrzejewski S, Dong Z, Blagih J, Annis MG, Omeroglu A, Gao D, Leung S, Amir E et al (2015) PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab 22:577–589CrossRefGoogle Scholar
  39. 39.
    Bu P, Chen KY, Xiang K, Johnson C, Crown SB, Rakhilin N, Ai Y, Wang L, Xi R, Astapova I et al (2018) Aldolase B-mediated fructose metabolism drives metabolic reprogramming of colon cancer liver metastasis. Cell Metab 27:1249–1262 e1244CrossRefGoogle Scholar
  40. 40.
    Morin A, Letouze E, Gimenez-Roqueplo AP, Favier J (2014) Oncometabolites-driven tumorigenesis: from genetics to targeted therapy. Int J Cancer 135:2237–2248CrossRefGoogle Scholar
  41. 41.
    Kumar S, Donti TR, Agnihotri N, Mehta K (2014) Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. Int J Cancer 134:2798–2807CrossRefGoogle Scholar
  42. 42.
    Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, Li Y, Chen YT, Yin F, Liao CP et al (2014) Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest 124:2891–2908CrossRefGoogle Scholar
  43. 43.
    Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145:732–744CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Tong Zhang
    • 1
  • Caixia Suo
    • 2
  • Chenyang Zheng
    • 1
  • Huafeng Zhang
    • 1
    Email author
  1. 1.Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life SciencesUniversity of Science and Technology of ChinaHefeiChina
  2. 2.Guangzhou First People’s Hospital, School of Medicine, Institutes for Life SciencesSouth China University of Technology of ChinaGuangzhouChina

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