The Metabolic Remodelling in Lung Cancer and Its Putative Consequence in Therapy Response

  • Ana Hipólito
  • Cindy Mendes
  • Jacinta SerpaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1219)


Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women. Conventional chemotherapy has failed to provide long-term benefits for many patients and in the past decade, important advances were made to understand the underlying molecular/genetic mechanisms of lung cancer, allowing the unfolding of several other pathological entities. Considering these molecular subtypes, and the appearance of promising targeted therapies, an effective personalized control of the disease has emerged, nonetheless benefiting a small proportion of patients. Although immunotherapy has also appeared as a new hope, it is still not accessible to the majority of patients with lung cancer.

The metabolism of energy and biomass is the basis of cellular survival. This is true for normal cells under physiological conditions and it is also true for pathophysiologically altered cells, such as cancer cells. Thus, knowledge of the metabolic remodelling that occurs in cancer cells in the sense of, on one hand, surviving in the microenvironment of the organ in which the tumour develops and, on the other hand, escaping from drugs conditioned microenvironment, is essential to understand the disease and to develop new therapeutic approaches.


Metabolic remodelling Tumor microenvironment Lung cancer Targeted therapy New therapeutic approaches 



The authors acknowledge iNOVA4Health – UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement.


  1. Abrams JA, Lee PC, Port JL et al (2008) Cigarette smoking and risk of lung metastasis from esophageal cancer. Cancer Epidemiol Biomark Prev 17:2707–2713. Scholar
  2. Achek A, Kwon H, Lee B, Yoo TH (2017) TLR4/MD2 specific peptides stalled in vivo LPS-induced immune exacerbation. Biomaterials 126:49–60. Scholar
  3. Adekola K, Rosen ST, Shanmugam M (2012) Glucose transporters in cancer metabolism. Curr Opin Oncol 24:650–654. Scholar
  4. Agrawal NR, Bukowski RM, Rybicki LA et al (2003) A phase I-II trial of polyethylene glycol-conjugated L-asparaginase in patients with multiple myeloma. Cancer 98:94–99. Scholar
  5. Altorki NK, Markowitz GJ, Gao D et al (2019) The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer 19:9–31CrossRefGoogle Scholar
  6. Amornsupak K, Insawang T, Thuwajit P et al (2014) Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells. BMC Cancer 14:955. Scholar
  7. Bak SP, Alonso A, Turk MJ, Berwin B (2008) Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol 46:258–268. Scholar
  8. Banat G-A, Tretyn A, Pullamsetti SS et al (2015) Immune and inflammatory cell composition of human lung cancer stroma. PLoS One 10:e0139073. Scholar
  9. Bhattacharya B, Mohd Omar MF, Soong R (2016) The Warburg effect and drug resistance. Br J Pharmacol 173:970–979. Scholar
  10. Bindea G, Mlecnik B, Tosolini M et al (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39:782–795. Scholar
  11. Biswas SK (2015) Metabolic reprogramming of immune cells in cancer progression. Immunity 43:435–449. Scholar
  12. Bremnes RM, Dønnem T, Al-Saad S et al (2011) The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol 6:209–217. Scholar
  13. Brunelli L, Caiola E, Marabese M et al (2014) Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells. Oncotarget 5:4722–4731. Scholar
  14. Cammann C, Rath A, Reichl U et al (2016) Early changes in the metabolic profile of activated CD8 + T cells. BMC Cell Biol 17(1):28. Scholar
  15. Candido J, Hagemann T (2013) Cancer-related inflammation. J Clin Immunol 33:79–84. Scholar
  16. Chang CH, Qiu J, O’Sullivan D et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241. Scholar
  17. Chapman NM, Shrestha S, Chi H (2017) Metabolism in immune cell differentiation and function. Adv Exp Med Biol 1011:1–85CrossRefGoogle Scholar
  18. Chaudhri VK, Salzler GG, Dick SA et al (2013) Metabolic alterations in lung cancer–associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol Cancer Res 11:579–592. Scholar
  19. Chen Z, Fillmore CM, Hammerman PS et al (2014a) Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14:535–546CrossRefGoogle Scholar
  20. Chen P-H, Cai L, Kim HS et al (2014b) Metabolic diversity in human non-small cell lung cancer. Cancer Metab 2.
  21. Chen F, Zhuang X, Lin L et al (2015) New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med 13:45CrossRefGoogle Scholar
  22. Choi H, Paeng JC, Kim DW et al (2013) Metabolic and metastatic characteristics of ALK-rearranged lung adenocarcinoma on FDG PET/CT. Lung Cancer 79:242–247. Scholar
  23. Ciamporcero E, Daga M, Pizzimenti S et al (2018) Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer. Free Radic Biol Med 115:447–457. Scholar
  24. Colla R, Izzotti A, De Ciucis C et al (2016) Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma. Oncotarget 7:70715–70737CrossRefGoogle Scholar
  25. Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ et al (2019) Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-β signaling. Free Radic Biol Med 130:163–173. Scholar
  26. Dagher Z, Ruderman N, Tornheim K, Ido Y (2001) Acute regulation of fatty acid oxidation and AMP-activated protein kinase in human umbilical vein endothelial cells. Circ Res 88:1276–1282. Scholar
  27. Dang EV, Barbi J, Yang H-Y et al (2011) Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146:772–784. Scholar
  28. Das Roy L, Pathangey LB, Tinder TL et al (2009) Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. Breast Cancer Res 11:R56. Scholar
  29. Davidson SM, Papagiannakopoulos T, Olenchock BA et al (2016) Environment impacts the metabolic dependencies of ras-driven non-small cell lung cancer. Cell Metab 23:517–528. Scholar
  30. Daynes RA, Jones DC (2002) Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2:748–759CrossRefGoogle Scholar
  31. De Alteriis E, Cartenì F, Parascandola P et al (2018) Revisiting the Crabtree/Warburg effect in a dynamic perspective: a fitness advantage against sugar-induced cell death. Cell Cycle 17(6):688–701. Scholar
  32. De Bock K, Georgiadou M, Carmeliet P (2013) Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18:634–647. Scholar
  33. DeWaal D, Nogueira V, Terry AR et al (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446. Scholar
  34. Dittmann K, Mayer C, Paasch A et al (2015) Nuclear EGFR renders cells radio-resistant by binding mRNA species and triggering a metabolic switch to increase lactate production. Radiother Oncol 116:431–437CrossRefGoogle Scholar
  35. Dranka BP, Hill BG, Darley-Usmar VM (2010) Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radic Biol Med 48:905–914. Scholar
  36. Dugnani E, Pasquale V, Bordignon C et al (2017) Integrating T cell metabolism in cancer immunotherapy. Cancer Lett 411:12–18. Scholar
  37. Dundar E, Oner U, Peker BC et al (2008) The significance and relationship between mast cells and tumour angiogenesis in non-small cell lung carcinoma. J Int Med Res 36:88–95. Scholar
  38. Dzobo K, Senthebane DA, Rowe A et al (2016) Cancer stem cell hypothesis for therapeutic innovation in clinical oncology? Taking the root out, not chopping the leaf. Omi A J Integr Biol 20:681–691. Scholar
  39. Ebos JML, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8(4):210–221CrossRefGoogle Scholar
  40. Fan TWM, Lane AN, Higashi RM et al (2009) Altered regulation of metabolic pathways in human lung cancer discerned by 13C stable isotope-resolved metabolomics (SIRM). Mol Cancer 8:41. Scholar
  41. Faubert B, Li KY, Cai L et al (2017) Lactate metabolism in human lung tumors. Cell 171:358–371.e9. Scholar
  42. Franses JW, Baker AB, Chitalia VC, Edelman ER (2011) Stromal endothelial cells directly influence cancer progression. Sci Transl Med 3:66ra5. Scholar
  43. Frauwirth KA, Riley JL, Harris MH et al (2002) The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–777. Scholar
  44. Gatenby RA, Gillies RJ (2007) Glycolysis in cancer: a potential target for therapy. Int J Biochem Cell Biol 39:1358–1366. Scholar
  45. Giatromanolaki A, Liousia M, Arelaki S et al (2017) Differential effect of hypoxia and acidity on lung cancer cell and fibroblast metabolism. Biochem Cell Biol 95:428–436. Scholar
  46. Gnanaprakasam JNR, Sherman JW, Wang R (2017) MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev 35:63–70. Scholar
  47. Gonçalves-Ribeiro S, Díaz-Maroto NG, Berdiel-Acer M et al (2016) Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells. Oncotarget 7:59766–59780. Scholar
  48. Graves EE, Maity A, Le QT (2010) The tumor microenvironment in non-small-cell lung cancer. Semin Radiat Oncol 20:156–163CrossRefGoogle Scholar
  49. Haemmerle G, Moustafa T, Woelkart G et al (2011) ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 17:1076–1085. Scholar
  50. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322CrossRefGoogle Scholar
  51. Hanahan D, Weinberg RA (2011) Leading edge review hallmarks of Cancer: the next generation. Cell 144:646–674. Scholar
  52. Harris AL (2002) Hypoxia — a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47. Scholar
  53. He X, Du S, Lei T et al (2017) PKM2 in carcinogenesis and oncotherapy. Oncotarget 8:110656–110670. Scholar
  54. Hensley CT, Faubert B, Yuan Q et al (2016) Metabolic heterogeneity in human lung tumors. Cell 164:681–694. Scholar
  55. Herbst RS, Onn A, Sandler A (2005) Angiogenesis and lung cancer: prognostic and therapeutic implications. J Clin Oncol 23:3243–3256. Scholar
  56. Hientz K, Mohr A, Bhakta-Guha D, Efferth T (2017) The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 8:8921–8946. Scholar
  57. Hirsch FR, Scagliotti GV, Mulshine JL et al (2017) Lung cancer: current therapies and new targeted treatments. Lancet 389:299–311. Scholar
  58. Hobbs GA, Der CJ, Rossman KL (2016) RAS isoforms and mutations in cancer at a glance. J Cell Sci 129:1287–1292. Scholar
  59. Hofman P (2017) ALK in non-small cell lung cancer (NSCLC) pathobiology, epidemiology, detection from tumor tissue and algorithm diagnosis in a daily practice. Cancers (Basel) 9:E107CrossRefGoogle Scholar
  60. Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13:233–245. Scholar
  61. Huang Q, Chen Z, Cheng P et al (2019) LYRM2 directly regulates complex I activity to support tumor growth in colorectal cancer by oxidative phosphorylation. Cancer Lett 455:36–47. Scholar
  62. I H, Cho J-Y (2015) Lung. Cancer Biomark:107–170Google Scholar
  63. Inamura K (2017) Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front Oncol 7.
  64. Ishii G (2017) Crosstalk between cancer associated fibroblasts and cancer cells in the tumor microenvironment after radiotherapy. EBioMedicine 17:7–8. Scholar
  65. Jacobs SR, Herman CE, Maciver NJ et al (2008) Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 180:4476–4486. Scholar
  66. Jang M, Kim SS, Lee J (2013) Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med 45:e45. Scholar
  67. Ji X, Qian J, Rahman SMJ et al (2018) xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene 37:5007–5019. Scholar
  68. Jiang T, Zhou M-L, Fan J (2018) Inhibition of GLUT-1 expression and the PI3K/Akt pathway to enhance the chemosensitivity of laryngeal carcinoma cells in vitro. Onco Targets Ther 11:7865–7872. Scholar
  69. Justus CR, Sanderlin EJ, Yang LV (2015) Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci 16:11055–11086. Scholar
  70. Kargl J, Busch SE, Yang GHY et al (2017) Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun 9:E468–E469. Scholar
  71. Karol SE, Janke LJ, Panetta JC et al (2019) Asparaginase combined with discontinuous dexamethasone improves antileukemic efficacy without increasing osteonecrosis in preclinical models. PLoS One 14:e0216328. Scholar
  72. Katayama R, Lovly CM, Shaw AT (2015) Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res 21:2227–2235. Scholar
  73. Kawada K, Toda K, Sakai Y (2017) Targeting metabolic reprogramming in KRAS-driven cancers. Int J Clin Oncol 22:651–659. Scholar
  74. Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480. Scholar
  75. Kelly MP, Jungbluth AA, Wu BW et al (2012) Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase. Br J Cancer 106:324–332. Scholar
  76. Keohavong P, Kahkonen B, Kinchington E et al (2011) K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation. Anticancer Res 31:2877–2882PubMedGoogle Scholar
  77. Kerr EM, Martins CP (2018) Metabolic rewiring in mutant Kras lung cancer. FEBS J 285:28–41CrossRefGoogle Scholar
  78. Kim SH, Song Y, Seo HR (2019) GSK-3β regulates the endothelial-to-mesenchymal transition via reciprocal crosstalk between NSCLC cells and HUVECs in multicellular tumor spheroid models. J Exp Clin Cancer Res 38:46. Scholar
  79. Kimmelman AC (2015) Metabolic dependencies in RAS-driven cancers. Clin Cancer Res 21:1828–1834. Scholar
  80. Koukourakis MI, Kalamida D, Mitrakas AG et al (2017) Metabolic cooperation between co-cultured lung cancer cells and lung fibroblasts. Lab Investig 97:1321–1331. Scholar
  81. Kwon O-H, Kang T-W, Kim J-H et al (2012) Pyruvate kinase M2 promotes the growth of gastric cancer cells via regulation of Bcl-xL expression at transcriptional level. Biochem Biophys Res Commun 423:38–44. Scholar
  82. Lee JH, Bhang DH, Beede A et al (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156:440–455. Scholar
  83. Lee HN, Ahn SM, Jang HH (2016) Cold-inducible RNA-binding protein promotes epithelial-mesenchymal transition by activating ERK and p38 pathways. Biochem Biophys Res Commun 477:1038–1044. Scholar
  84. Lemjabbar-Alaoui H, Hassan OU, Yang Y-W, Buchanan P (2015) Lung cancer: biology and treatment options. Biochim Biophys Acta – Rev Cancer 1856:189–210. Scholar
  85. Li W, Gao F, Ma X et al (2017) Deguelin inhibits non-small cell lung cancer via down-regulating hexokinases II-mediated glycolysis. Oncotarget 8:32586–32599. Scholar
  86. Lis P, Dyląg M, Niedźwiecka K et al (2016) The HK2 dependent “Warburg Effect” and mitochondrial oxidative phosphorylation in cancer: targets for effective therapy with 3-bromopyruvate. Molecules 21:E1730. Scholar
  87. Liu Y, Cao Y, Zhang W et al (2012) A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 11:1672–1682. Scholar
  88. Liu Y, Murray-Stewart T, Casero RA et al (2017) Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth. Int J Oncol 50:2011–2023. Scholar
  89. Lobb RJ, van Amerongen R, Wiegmans A et al (2017) Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance. Int J Cancer 141:614–620. Scholar
  90. Lopes-Coelho F, Gouveia-Fernandes S, Nunes SC, Serpa J (2017) Metabolic dynamics in breast cancer: cooperation between cancer and stromal breast cancer cells. J Clin Breast Cancer Res 1:1–7Google Scholar
  91. Lopes-Coelho F, Gouveia-Fernandes S, Serpa J (2018) Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression. Tumor Biol 40:1–15. Scholar
  92. Lujan DA, Ochoa JL, Hartley RS (2018) Cold-inducible RNA binding protein in cancer and inflammation. Wiley Interdiscip Rev RNA 9:e1462. Scholar
  93. Lyssiotis CA, Kimmelman AC (2017) Metabolic interactions in the tumor microenvironment. Trends Cell Biol 27:863–875. Scholar
  94. Makinoshima H, Takita M, Matsumoto S et al (2014) Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma. J Biol Chem 289:20813–20823. Scholar
  95. Mallappa S, Neeli PK, Karnewar S, Kotamraju S (2019) Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: relevance of statins in chemosensitization. Mol Carcinog 58:1118–1133. Scholar
  96. Mariathasan S, Hewton K, Monack DM et al (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218. Scholar
  97. Martín-Bernabé A, Cortés R, Lehmann SG et al (2014) Quantitative proteomic approach to understand metabolic adaptation in non-small cell lung cancer. J Proteome Res 13:4695–4704. Scholar
  98. Martinez-Outschoorn UE, Lisanti MP, Sotgia F (2014) Catabolic cancer-associated fibroblasts (CAFs) transfer energy and biomass to anabolic cancer cells, Fueling Tumor Growth. Semin Cancer Biol 25:1–13. Scholar
  99. Mazat J-P, Ransac S (2019) The fate of glutamine in human metabolism. The interplay with glucose in proliferating cells. Meta 9:81. Scholar
  100. Melosky B, Juergens R, Hirsh V et al (2019) Amplifying outcomes: checkpoint inhibitor combinations in first-line non-small cell lung cancer. Oncologist theoncologist.2019-0027. Scholar
  101. Michael M, Doherty MM (2005) Tumoral drug metabolism: overview and its implications for cancer therapy. J Clin Oncol 23:205–229. Scholar
  102. Migita T, Narita T, Nomura K et al (2008) ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 68:8547–8554. Scholar
  103. Min HY, Lee HY (2018) Oncogene-driven metabolic alterations in cancer. Biomol Ther 26:45–56. Scholar
  104. Min JW, Il KK, Kim H-A et al (2013) INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells. Biochem Biophys Res Commun 440:137–142. Scholar
  105. Mittal V, El Rayes T, Narula N et al (2016a) The microenvironment of lung cancer and therapeutic implications. Adv Exp Med Biol 890:75–110CrossRefGoogle Scholar
  106. Mittal V, El Rayes T, Navneet N (2016b) The microenvironment of lung cancer and therapeutic implications. Adv Exp Med Biol 890:75–110CrossRefGoogle Scholar
  107. Momcilovic M, Bailey ST, Lee JT et al (2017) Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR mutant lung cancer. Cell Rep 18:601–610. Scholar
  108. Morales-Nebreda L, Misharin AV, Perlman H, Scott Budinger GR (2015) The heterogeneity of lung macrophages in the susceptibility to disease. Eur Respir Rev 24:505–509. Scholar
  109. Murin S, Inciardi J (2003) Cigarette smoking and the risk of pulmonary metastasis from breast cancer. Chest 119:1635–1640. Scholar
  110. Nagarajan A, Malvi P, Wajapeyee N (2016) Oncogene-directed alterations in cancer cell metabolism. Trends Cancer 2:365–377. Scholar
  111. Nunes SC, Serpa J (2018) Glutathione in ovarian cancer: a double-edged sword. Int J Mol Sci 19:E1882CrossRefGoogle Scholar
  112. Nunes SC, Ramos C, Lopes-Coelho F et al (2018) Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Sci Rep 8:9513. Scholar
  113. O’Reilly S, van Laar JM (2018) Targeting the TLR4-MD2 axis in systemic sclerosis. Nat Rev Rheumatol 14:564–566. Scholar
  114. Onetti R, Baulida J, Bassols A (1997) Increased glucose transport in ras-transformed fibroblasts: a possible role for N-glycosylation of GLUT1. FEBS Lett 407:267–270. Scholar
  115. Ott PA, Carvajal RD, Pandit-Taskar N et al (2013) Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Investig New Drugs 31:425–434. Scholar
  116. Otto Warburg B, Wind F, Negelein N (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530. Scholar
  117. Palsson-McDermott EM, O’Neill LAJ (2013) The Warburg effect then and now: from cancer to inflammatory diseases. BioEssays 35:965–973. Scholar
  118. Papandreou I, Cairns RA, Fontana L et al (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197. Scholar
  119. Patra KC, Wang Q, Bhaskar PT et al (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213–228. Scholar
  120. Pavlides S, Whitaker-Menezes D, Castello-Cros R et al (2009) The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001. Scholar
  121. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47. Scholar
  122. Phipps AI, Buchanan DD, Makar KW et al (2013) KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers. Br J Cancer 108:1757–1764. Scholar
  123. Pikor LA, Ramnarine VR, Lam S, Lam WL (2013) Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer 82:179–189CrossRefGoogle Scholar
  124. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7:803–815. Scholar
  125. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 19:1423–1437. Scholar
  126. Qin A, Coffey DG, Warren EH, Ramnath N (2016) Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer. Cancer Med 5:2567–2578. Scholar
  127. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437. Scholar
  128. Queiroz KCS, Shi K, Duitman J et al (2014) Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. Int J Cancer 135:2294–2304. Scholar
  129. Rabold K, Netea MG, Adema GJ, Netea-Maier RT (2017) Cellular metabolism of tumor-associated macrophages – functional impact and consequences. FEBS Lett 591:3022–3041. Scholar
  130. Rodriguez PC, Zea AH, DeSalvo J et al (2003) L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171:1232–1239. Scholar
  131. Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109:1568–1573. Scholar
  132. Rycaj K, Tang DG (2015) Cell-of-origin of cancer versus cancer stem cells: assays and interpretations. Cancer Res 75:4003–4011. Scholar
  133. Salem A, Asselin M-C, Reymen B et al (2018) Targeting hypoxia to improve non–small cell lung cancer outcome. JNCI J Natl Cancer Inst 110:14–30. Scholar
  134. Schoors S, Bruning U, Missiaen R et al (2015) Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520:192–197. Scholar
  135. Sellers K, Fox MP, Ii MB et al (2015) Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J Clin Invest 125:687–698. Scholar
  136. Sen DB, Nolan DJ, Guo P et al (2011) Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell 147:539–553. Scholar
  137. Serpa J, Dias S (2011) Metabolic cues from the microenvironment act as a major selective factor for cancer progression and metastases formation. Cell Cycle 10:180–181. Scholar
  138. Shi LZ, Wang R, Huang G et al (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367–1376. Scholar
  139. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629. Scholar
  140. Shigematsu H, Lin L, Takahashi T et al (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. JNCI J Natl Cancer Inst 97:339–346. Scholar
  141. Son J, Lyssiotis CA, Ying H et al (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105. Scholar
  142. Song H, Yao E, Lin C et al (2012) Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci 109:17531–17536. Scholar
  143. Song H, Yao E, Lin C et al (2014) Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15:123–138. Scholar
  144. Song K, Li M, Xu X et al (2016) Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia. Oncol Lett 12:334–342. Scholar
  145. Spees JL, Olson SD, Whitney MJ, Prockop DJ (2006) Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci 103:1283–1288. Scholar
  146. Sriraman SK, Aryasomayajula B, Torchilin VP (2014) Barriers to drug delivery in solid tumors. Tissue Barriers 2:e29528. Scholar
  147. Stathopoulos GT, Sherrill TP, Han W et al (2008) Host nuclear factor- B activation potentiates lung cancer metastasis. Mol Cancer Res 6:364–371. Scholar
  148. Stoll G, Kremer M, Bloy N et al (2019) Metabolic enzymes expressed by cancer cells impact the immune infiltrate. Oncoimmunology 8:e1571389. Scholar
  149. Storozhuk Y, Hopmans SN, Sanli T et al (2013) Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br J Cancer 108:2021–2032. Scholar
  150. Subramanian J, Govindan R (2008) Molecular genetics of lung cancer in people who have never smoked. Lancet Oncol 9:676–682. Scholar
  151. Teuwen LA, Draoui N, Dubois C, Carmeliet P (2017) Endothelial cell metabolism: an update anno 2017. Curr Opin Hematol 24:240–247. Scholar
  152. Thorens B, Mueckler M (2010) Glucose transporters in the 21st century. Am J Physiol Endocrinol Metab 298:E141–E145. Scholar
  153. Torok S, Hegedus B, Laszlo V et al (2011) Lung cancer in never smokers. Future Oncol 7:1195–1211. Scholar
  154. Tran S, Ready N, Krug LM, Pietanza MC, Jungbluth AA, Pan LS, Venhaus RR, Hoffman EW, Peters A-M, Dukelow K, Bomalaski JS, Wu B-W, LJO (2012) Phase II study of ADI-PEG 20 in patients with relapsed sensitive or refractory small cell lung cancer. J Clin Oncol 30:e17558–e17558Google Scholar
  155. Valadi H, Ekström K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. Scholar
  156. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. Scholar
  157. Vander Linden C, Corbet C (2019) Reconciling environment-mediated metabolic heterogeneity with the oncogene-driven cancer paradigm in precision oncology. Semin Cell Dev Biol. Scholar
  158. Vansteenkiste J, Wauters E, Reymen B et al (2019) Current status of immune checkpoint inhibition in early stage NSCLC. Ann Oncol 30:1244–1253. Scholar
  159. Vegliante R, Di Leo L, Ciccarone F, Ciriolo MR (2018) Hints on ATGL implications in cancer: beyond bioenergetic clues. Cell Death Dis 9:316. Scholar
  160. Vukovic V, Tannock IF (1997) Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan. Br J Cancer 75:1167–1172CrossRefGoogle Scholar
  161. Wang R, Dillon CP, Shi LZ et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882. Scholar
  162. Wang H, Wang L, Zhang Y et al (2016) Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. Cancer Cell Int 16(9):9. Scholar
  163. Wang L, Cao L, Wang H et al (2017a) Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway. Oncotarget 8:76116–76128. Scholar
  164. Wang X, Zhang F, Wu X-R (2017b) Inhibition of pyruvate kinase M2 markedly reduces chemoresistance of advanced bladder cancer to cisplatin. Sci Rep 7:45983. Scholar
  165. Wang Y, Hao F, Nan Y et al (2018) PKM2 inhibitor Shikonin overcomes the cisplatin resistance in bladder cancer by inducing necroptosis. Int J Biol Sci 14:1883–1891. Scholar
  166. Wang L, Li X, Ren Y et al (2019a) Cancer-associated fibroblasts contribute to cisplatin resistance by modulating ANXA 3 in lung cancer cells. Cancer Sci 110:1609–1620. Scholar
  167. Wang R, Lou X, Feng G et al (2019b) IL-17A-stimulated endothelial fatty acid β-oxidation promotes tumor angiogenesis. Life Sci 229:46–56. Scholar
  168. Warburg O (1956) On the origin of cancer cells. Science 123:309–314. Scholar
  169. Warburg O, Minami S (1923) Versuche an Überlebendem Carcinomgewebe. Klin Wochenschr 2:776–777CrossRefGoogle Scholar
  170. West AP (2017) Mitochondrial dysfunction as a trigger of innate immune responses and inflammation. Toxicology 391:54–63. Scholar
  171. Woo CG, Seo S, Kim SW et al (2016) Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK -rearranged non–small cell lung cancer. Ann Oncol:mdw693. Scholar
  172. Xu Y-Y, Wu T-T, Zhou S-H et al (2014) Apigenin suppresses GLUT-1 and p-AKT expression to enhance the chemosensitivity to cisplatin of laryngeal carcinoma Hep-2 cells: an in vitro study. Int J Clin Exp Pathol 7:3938–3947PubMedPubMedCentralGoogle Scholar
  173. Yan H, Guo B-Y, Zhang S (2016) Cancer-associated fibroblasts attenuate Cisplatin-induced apoptosis in ovarian cancer cells by promoting STAT3 signaling. Biochem Biophys Res Commun 470:947–954. Scholar
  174. Yau T, Cheng PN, Chan P et al (2013) A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma. Investig New Drugs 31:99–107. Scholar
  175. Yeldag G, Rice A, Del Río Hernández A (2018) Chemoresistance and the self-maintaining tumor microenvironment. Cancers (Basel) 10. Scholar
  176. Ying H, Kimmelman AC, Lyssiotis CA et al (2012) Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149:656–670. Scholar
  177. Ying L, Zhu Z, Xu Z et al (2015) Cancer associated fibroblast-derived hepatocyte growth factor inhibits the paclitaxel-induced apoptosis of lung cancer A549 cells by up-regulating the PI3K/Akt and GRP78 signaling on a microfluidic platform. PLoS One 10:e0129593. Scholar
  178. Yuan S, Qiao T, Zhuang X et al (2016) Knockdown of the M2 isoform of pyruvate kinase (PKM2) with shRNA enhances the effect of docetaxel in human NSCLC cell lines in vitro. Yonsei Med J 57:1312–1323. Scholar
  179. Zengin M (2019) Prognostic role of tumour-infiltrating T lymphocytes in stage IIA (T3N0) colon cancer: a broad methodological study in a fairly homogeneous population. Ann Diagn Pathol 41:69–78. Scholar
  180. Zhang Z, Stiegler AL, Boggon TJ, Kobayashi S (2010) EGFR-mutated lung cancer: a paradigm of molecular oncology abstract: abbreviations used. Oncotarget 1:497–514CrossRefGoogle Scholar
  181. Zhang WC, Ng SC, Yang H et al (2012) Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148:259–272. Scholar
  182. Zhang Y-L, Yuan J-Q, Wang K-F et al (2016) The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 7:78985–78993. Scholar
  183. Zhang Y, Wang DC, Shi L et al (2017a) Genome analyses identify the genetic modification of lung cancer subtypes. Semin Cancer Biol 42:20–30. Scholar
  184. Zhang J, Song F, Zhao X et al (2017b) EGFR modulates monounsaturated fatty acid synthesis through phosphorylation of SCD1 in lung cancer. Mol Cancer 16:127. Scholar
  185. Zhang L, Yao Y, Zhang S et al (2019) Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma. Sci Transl Med 11:eaau1167. Scholar
  186. Zhao J (2016) Cancer stem cells and chemoresistance: the smartest survives the raid. Pharmacol Ther 160:145–158. Scholar
  187. Zhou Y, Wen H, Gu L et al (2017) Aminoglucose-functionalized, redox-responsive polymer nanomicelles for overcoming chemoresistance in lung cancer cells. J Nanobiotechnol 15:87. Scholar
  188. Zhu H, Wu J, Zhang W et al (2016) PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. Sci Rep 6:30788. Scholar
  189. Zimmer AD, Walbrecq G, Kozar I et al (2016) Phosphorylation of the pyruvate dehydrogenase complex precedes HIF-1-mediated effects and pyruvate dehydrogenase kinase 1 upregulation during the first hours of hypoxic treatment in hepatocellular carcinoma cells. Hypoxia 4:135–145. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisbonPortugal
  2. 2.Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG)LisbonPortugal

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