Skip to main content
SpringerLink
Log in

Progression of Lung Cancer: Role of Hypoxia and the Metabolic Tumor Microenvironment

  • Chapter
  • First Online:
Mechanisms of Molecular Carcinogenesis – Volume 1

  • 736 Accesses

Abstract

Hypoxia and nutrient deprivation are frequently present in the microenvironment of solid tumors, like lung cancer. Poor perfusion due to aberrant tumor vessels and large diffusion distances, as well as high consumption (e.g., of glucose), are the underlying causes. In addition, lactate accumulates, creating an acidic tumor microenvironment. The cancer-promoting role of hypoxia and the underlying molecular mechanisms are quite well characterized: activation of angiogenesis via upregulation of vascular endothelial growth factor (VEGF), induction of apoptosis resistance, selection of resistant clones under severe hypoxia, and others. In contrast, the impact of nutrient deprivation and lactate accumulation on cancer progression and cancer cell metabolism are less well understood. In the present chapter, we summarize recent clinical and preclinical data on hypoxia and nutrient deprivation in cancer with special emphasis on lung cancer. The contribution of cofactors, like anemia, and the consequences for carcinogenesis and cell metabolism are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ramalingam SS, Owonikoko TK, Khuri FR. Lung cancer: new biological insights and recent therapeutic advances. CA Cancer J Clin. 2011;61(2):91–112.

    Article  PubMed  Google Scholar 

  2. Socinski MA. Cytotoxic chemotherapy in advanced non-small cell lung cancer: a review of standard treatment paradigms. Clin Cancer Res. 2004;10:4210s–4s.

    Article  CAS  PubMed  Google Scholar 

  3. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382:709–19.

    Article  CAS  PubMed  Google Scholar 

  4. Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist. 2008;13(Suppl 3):21–6.

    Article  CAS  PubMed  Google Scholar 

  5. Cantor JR, Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2012;2(10):881–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  7. Ackerman D, Simon MC. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 2014;24(8):472–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49(23):6449–65.

    CAS  PubMed  Google Scholar 

  9. Cagle PT, Allen TC. Advances in surgical pathology: lung cancer. Philadelphia: Wolters Kluwer Health; 2010.

    Google Scholar 

  10. Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal. 2007;9(8):1221–35.

    Article  CAS  PubMed  Google Scholar 

  11. Hardee ME, Dewhirst MW, Agarwal N, Sorg BS. Novel imaging provides new insights into mechanisms of oxygen transport in tumors. Curr Mol Med. 2009;9(4):435–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Torres Filho IP, Leunig M, Yuan F, Intaglietta M, Jain RK. Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice. Proc Natl Acad Sci U S A. 1994;91(6):2081–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Karoor V, Le M, Merrick D, Fagan KA, Dempsey EC, Miller YE. Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism. Cancer Prev Res (Phila). 2012;5(8):1061–71.

    Article  CAS  Google Scholar 

  14. Le QT, Chen E, Salim A, Cao H, Kong CS, Whyte R, et al. An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers. Clin Cancer Res. 2006;12(5):1507–14.

    Article  CAS  PubMed  Google Scholar 

  15. Graves EE, Vilalta M, Cecic IK, Erler JT, Tran PT, Felsher D, et al. Hypoxia in models of lung cancer: implications for targeted therapeutics. Clin Cancer Res. 2010;16(19):4843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yip C, Blower PJ, Goh V, Landau DB, Cook GJ. Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging. 2015;42(6):956–76.

    Article  CAS  PubMed  Google Scholar 

  17. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410.

    Article  CAS  PubMed  Google Scholar 

  18. Wohlkoenig C, Leithner K, Deutsch A, Hrzenjak A, Olschewski A, Olschewski H. Hypoxia-induced cisplatin resistance is reversible and growth rate independent in lung cancer cells. Cancer Lett. 2011;308(2):134–43.

    Article  CAS  PubMed  Google Scholar 

  19. Calabro E, Randi G, La Vecchia C, Sverzellati N, Marchiano A, Villani M, et al. Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes. Eur Respir J. 2010;35(1):146–51.

    Article  CAS  PubMed  Google Scholar 

  20. McIntyre A, Harris AL. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med. 2015;7(4):368–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shimoda LA, Semenza GL. HIF and the lung: role of hypoxia-inducible factors in pulmonary development and disease. Am J Respir Crit Care Med. 2011;183(2):152–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liao D, Corle C, Seagroves TN, Johnson RS. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 2007;67(2):563–72.

    Article  CAS  PubMed  Google Scholar 

  23. Bolli GB. How to ameliorate the problem of hypoglycemia in intensive as well as nonintensive treatment of type 1 diabetes. Diabetes Care. 1999;22(Suppl 2):B43–52.

    PubMed  Google Scholar 

  24. Rocha CM, Barros AS, Goodfellow BJ, Carreira IM, Gomes A, Sousa V, et al. NMR metabolomics of human lung tumours reveals distinct metabolic signatures for adenocarcinoma and squamous cell carcinoma. Carcinogenesis. 2015;36(1):68–75.

    Article  CAS  PubMed  Google Scholar 

  25. Rocha CM, Barros AS, Gil AM, Goodfellow BJ, Humpfer E, Spraul M, et al. Metabolic profiling of human lung cancer tissue by 1H high resolution magic angle spinning (HRMAS) NMR spectroscopy. J Proteome Res. 2010;9(1):319–32.

    Article  CAS  PubMed  Google Scholar 

  26. Duarte IF, Rocha CM, Barros AS, Gil AM, Goodfellow BJ, Carreira IM, et al. Can nuclear magnetic resonance (NMR) spectroscopy reveal different metabolic signatures for lung tumours? Virchows Arch. 2010;457(6):715–25.

    Article  CAS  PubMed  Google Scholar 

  27. Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009;69(11):4918–25.

    Article  CAS  PubMed  Google Scholar 

  28. Wang L, Chen J, Chen L, Deng P, Bu Q, Xiang P, et al. 1H-NMR based metabonomic profiling of human esophageal cancer tissue. Mol Cancer. 2013;12:12–25.

    Article  Google Scholar 

  29. Ziebart T, Walenta S, Kunkel M, Reichert TE, Wagner W, Mueller-Klieser W. Metabolic and proteomic differentials in head and neck squamous cell carcinomas and normal gingival tissue. J Cancer Res Clin Oncol. 2011;137(2):193–9.

    Article  CAS  PubMed  Google Scholar 

  30. Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 2014;508(7494):108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Walenta S, Snyder S, Haroon ZA, Braun RD, Amin K, Brizel D, et al. Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model. Int J Radiat Oncol Biol Phys. 2001;51(3):840–8.

    Article  CAS  PubMed  Google Scholar 

  32. Schroeder T, Yuan H, Viglianti BL, Peltz C, Asopa S, Vujaskovic Z, et al. Spatial heterogeneity and oxygen dependence of glucose consumption in R3230Ac and fibrosarcomas of the Fischer 344 rat. Cancer Res. 2005;65(12):5163–71.

    Article  CAS  PubMed  Google Scholar 

  33. Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012;23(4):352–61.

    Article  CAS  PubMed  Google Scholar 

  34. Nakamura W, Hosoda S. The absence of glucose in Ehrlich ascites tumor cells and fluid. Biochim Biophys Acta. 1968;158(2):212–8.

    Article  CAS  PubMed  Google Scholar 

  35. Fabian C, Koetz L, Favaro E, Indraccolo S, Mueller-Klieser W, Sattler UG. Protein profiles in human ovarian cancer cell lines correspond to their metabolic activity and to metabolic profiles of respective tumor xenografts. FEBS J. 2012;279(5):882–91.

    Article  CAS  PubMed  Google Scholar 

  36. Brown RS, Leung JY, Kison PV, Zasadny KR, Flint A, Wahl RL. Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer. J Nucl Med. 1999;40(4):556–65.

    CAS  PubMed  Google Scholar 

  37. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491(7424):364–73.

    Article  CAS  PubMed  Google Scholar 

  39. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.

    Article  CAS  PubMed  Google Scholar 

  40. DeBerardinis RJ, Thompson CB. Cellular metabolism and disease: what do metabolic outliers teach us? Cell. 2012;148(6):1132–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kalhan SC, Hanson RW. Resurgence of serine: an often neglected but indispensable amino acid. J Biol Chem. 2012;287(24):19786–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 2010;24(24):2784–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schlappack OK, Zimmermann A, Hill RP. Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. Br J Cancer. 1991;64(4):663–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Beckonert O, Monnerjahn J, Bonk U, Leibfritz D. Visualizing metabolic changes in breast-cancer tissue using 1H-NMR spectroscopy and self-organizing maps. NMR Biomed. 2003;16(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  47. Ellingsen C, Walenta S, Hompland T, Mueller-Klieser W, Rofstad EK. The microenvironment of cervical carcinoma xenografts: associations with lymph node metastasis and its assessment by DCE-MRI. Transl Oncol. 2013;6(5):607–17.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17(4):351–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouyssegur J, Mazure NM. Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Front Oncol. 2012;2:18.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res. 2015;21(4):680–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Icard P, Kafara P, Steyaert JM, Schwartz L, Lincet H. The metabolic cooperation between cells in solid cancer tumors. Biochim Biophys Acta. 2014;1846(1):216–25.

    CAS  PubMed  Google Scholar 

  52. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 7th ed. New York: W.H. Freeman; 2011.

    Google Scholar 

  53. Yang J, Kalhan SC, Hanson RW. What is the metabolic role of phosphoenolpyruvate carboxykinase? J Biol Chem. 2009;284(40):27025–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Leithner K, Hrzenjak A, Trotzmuller M, Moustafa T, Kofeler HC, Wohlkoenig C, et al. PCK2 activation mediates an adaptive response to glucose depletion in lung cancer. Oncogene. 2015;34(8):1044–50.

    Article  CAS  PubMed  Google Scholar 

  55. Mendez-Lucas A, Hyrossova P, Novellasdemunt L, Vinals F, Perales JC. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient availability. J Biol Chem. 2014;289(32):22090–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vincent EE, Sergushichev A, Griss T, Gingras MC, Samborska B, Ntimbane T, et al. Mitochondrial phosphoenolpyruvate carboxykinase regulates metabolic adaptation and enables glucose-independent tumor growth. Mol Cell. 2015;60(2):195–207.

    Google Scholar 

  57. White E. The role for autophagy in cancer. J Clin Invest. 2015;125(1):42–6.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015;34(7):856–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40(2):280–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ramirez-Peinado S, Leon-Annicchiarico CL, Galindo-Moreno J, Iurlaro R, Caro-Maldonado A, Prehn JH, et al. Glucose-starved cells do not engage in prosurvival autophagy. J Biol Chem. 2013;288(42):30387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fan TW, Lane AN, Higashi RM, Farag MA, Gao H, Bousamra M, et al. Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM). Mol Cancer. 2009;8:41.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Polet F, Feron O. Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force. J Intern Med. 2013;273(2):156–65.

    Article  CAS  PubMed  Google Scholar 

  63. Peppicelli S, Bianchini F, Calorini L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014;33(2–3):823–32.

    Article  CAS  PubMed  Google Scholar 

  64. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118(12):3930–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Boidot R, Vegran F, Meulle A, Le Breton A, Dessy C, Sonveaux P, et al. Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res. 2012;72(4):939–48.

    Article  CAS  PubMed  Google Scholar 

  66. Halestrap AP. The monocarboxylate transporter family—structure and functional characterization. IUBMB Life. 2012;64(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  67. Polanski R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014;20(4):926–37.

    Article  CAS  PubMed  Google Scholar 

  68. Toma-Dasu I, Dasu A. Quantitative hypoxia imaging for treatment planning of radiotherapy. Adv Exp Med Biol. 2014;812:143–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, A-8036, Austria

    Katharina Leithner & Horst Olschewski

Authors
  1. Katharina Leithner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Horst Olschewski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katharina Leithner .

Editor information

Editors and Affiliations

  1. Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany

    Johannes Haybaeck

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Leithner, K., Olschewski, H. (2017). Progression of Lung Cancer: Role of Hypoxia and the Metabolic Tumor Microenvironment. In: Haybaeck, J. (eds) Mechanisms of Molecular Carcinogenesis – Volume 1. Springer, Cham. https://doi.org/10.1007/978-3-319-53659-0_18

Download citation

Publish with us

Policies and ethics

Search

Navigation