Tumor Microenvironment – Selective Pressures Boosting Cancer Progression

  • Sofia C. Nunes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1219)


In 2018, 9.6 million deaths from cancer were estimated, being this disease the second leading cause of death worldwide. Notwithstanding all the efforts developed in prevention, diagnosis and new treatment approaches, chemoresistance seems to be inevitable, leading to cancer progression, recurrence and affecting the outcome of the disease. As more and more evidence support that cancer is an evolutionary and ecological process, this concept is rarely applied in the clinical context. In fact, cancer cells emerge and progress within an ecological niche – the tumor microenvironment – that is shared with several other cell types and that is continuously changing. Therefore, the tumor microenvironment imposes several selective pressures on cancer cells such as acidosis, hypoxia, competition for space and resources, immune predation and anti-cancer therapies, that cancer cells must be able to adapt to or will face extinction.

In here, the role of the tumor microenvironment selective pressures on cancer progression will be discussed, as well as the targeting of its features/components as strategies to fight cancer.


Cancer Evolution Microenvironment Metabolic selection 



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. Achard C, Surendran A, Wedge M-E et al (2018) Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine 31:17–24. Scholar
  2. Agarwal M, Bhadauria AS (2013) A generalised prey-predator type model of immunogenic cancer with the effect of immunotherapy. Int J Eng Sci Technol 5:66–84. Scholar
  3. Aktipis CA, Kwan VSY, Johnson KA et al (2011) Overlooking evolution: a systematic analysis of Cancer relapse and therapeutic resistance research. PLoS One 6:e26100. Scholar
  4. Aktipis CA, Boddy AM, Jansen G et al (2015) Cancer across the tree of life: cooperation and cheating in multicellularity. Philos Trans R Soc B Biol Sci 370:1–21. Scholar
  5. Albano G, Giorno V, Saturnino C (2007) A prey-predator model for immune response and drug resistance in tumor growth. In: Moreno Díaz R, Pichler FQAA (eds) Computer aided systems theory – EUROCAST 2007. Lecture notes in computer science, vol 4739. Springer, Berlin/Heidelberg, pp 171–178Google Scholar
  6. Alexandre J, Batteux F, Nicco C et al (2006) Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer 119:41–48. Scholar
  7. Alfarouk KO, Ibrahim ME, Gatenby RA, Brown JS (2013) Riparian ecosystems in human cancers. Evol Appl 6:46–53. Scholar
  8. Allen E, Ville PḾ, Warren CM et al (2016) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15:1144–1160. Scholar
  9. Angelova M, Mlecnik B, Vasaturo A et al (2018) Evolution of metastases in space and time under immune selection. Cell 175:751–765.e16. Scholar
  10. Archetti M, Ferraro DA, Christofori G (2015) Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer. Proc Natl Acad Sci U S A 112:1833–1838. Scholar
  11. Axelrod R, Axelrod DE, Pienta KJ (2006) Evolution of cooperation among tumor cells. Proc Natl Acad Sci U S A 103:13474–13479. Scholar
  12. Babbs CF (2012) Predicting success or failure of immunotherapy for cancer: insights from a clinically applicable mathematical model. Am J Cancer Res 2:204–213PubMedGoogle Scholar
  13. Balamurugan K (2016) HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer 138:1058–1066. Scholar
  14. Barker HE, Paget JTE, Khan AA, Harrington KJ (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15:409–425. Scholar
  15. Bartosh TJ, Ullah M, Zeitouni S et al (2016) Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). Proc Natl Acad Sci U S A 113:E6447–E6456. Scholar
  16. Bergman A, Gligorijevic B (2015) Niche construction game cancer cells play. Eur Phys J Plus 130:203–215. Scholar
  17. Bhandari V, Hoey C, Liu LY et al (2019) Molecular landmarks of tumor hypoxia across cancer types. Nat Genet 51:308–318. Scholar
  18. Binnewies M, Roberts EW, Kersten K et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24:541–550. Scholar
  19. Bray F, Ferlay J, Soerjomataram I et al (2018) Global Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. Scholar
  20. Bristow RG, Hill RP (2008) Hypoxia and metabolism: hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–192. Scholar
  21. Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255:197–200. Scholar
  22. Chang C-H, 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
  23. Chapman A, del Ama LF, Ferguson J et al (2014) Heterogeneous tumor subpopulations cooperate to drive invasion. Cell Rep 8:688–695. Scholar
  24. Chauhan VP, Chen IX, Tong R et al (2019) Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc Natl Acad Sci 116:10674–10680. Scholar
  25. Chen H, He X (2015) The convergent cancer evolution toward a single cellular destination. Mol Biol Evol 33:4–12. Scholar
  26. Chen H, Lin F, Xing K, He X (2015a) The reverse evolution from multicellularity to unicellularity during carcinogenesis. Nat Commun 6:1–9. Scholar
  27. Chen Y, Zhang L, Liu W, Liu X (2015b) Prognostic significance of the tumor-stroma ratio in epithelial ovarian cancer. Biomed Res Int 2015:1–8. Scholar
  28. Chen H, Xu L, Li L et al (2018) Inhibiting the CD8+ T cell infiltration in the tumor microenvironment after radiotherapy is an important mechanism of radioresistance. Sci Rep 8:1–10. Scholar
  29. Choi SYC, Collins CC, Gout PW, Wang Y (2013) Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol 230:350–355. Scholar
  30. Cleary AS, Leonard TL, Gestl SA, Gunther EJ (2014) Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 508:113–117. Scholar
  31. Corbet C, Feron O (2017) Tumour acidosis: from the passenger to the driver’s seat. Nat Rev Cancer 17:577–593. Scholar
  32. Crespi B, Summers K (2005) Evolutionary biology of cancer. Trends Ecol Evol 20:545–552. Scholar
  33. Dagogo-Jack I, Shaw AT (2017) Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 15:81–94. Scholar
  34. Damaghi M, Tafreshi NK, Lloyd MC et al (2015) Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane. Nat Commun 6:1–13. Scholar
  35. Damgaci S, Ibrahim-Hashim A, Enriquez-Navas PM et al (2018) Hypoxia and acidosis: immune suppressors and therapeutic targets. Immunology 154:354–362. Scholar
  36. Darwin C (1859) The origin of species (text). Pennsylvania State University 448 p.
  37. Dasari S, Tchounwou BP (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. Scholar
  38. Datta M, Coussens LM, Nishikawa H et al (2019) Reprogramming the tumor microenvironment to improve immunotherapy: emerging strategies and combination therapies. Am Soc Clin Oncol Educ B 39:165–174. Scholar
  39. De Kruijf EM, Van Nes JGH, Van De Velde CJH et al (2011) Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. Breast Cancer Res Treat 125:687–696. Scholar
  40. Denduluri SK, Idowu O, Wang Z et al (2015) Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis 2:13–25. Scholar
  41. Di Gregorio A, Bowling S, Rodriguez TA (2016) Cell competition and its role in the regulation of cell fitness from development to cancer. Dev Cell 38:621–634. Scholar
  42. Enriquez-Navas PM, Kam Y, Das T et al (2016) Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer. Sci Transl Med 8:1–9. Scholar
  43. Fais S, Overholtzer M (2018) Cell-in-cell phenomena in cancer. Nat Rev Cancer 18:758–766. Scholar
  44. Fitzgerald DM, Hastings PJ, Rosenberg SM (2017) Stress-induced mutagenesis: implications in cancer and drug resistance. Ann Rev Cancer Biol 1:119–140. Scholar
  45. Fitzmaurice C, Dicker D, Pain A et al (2015) The global burden of cancer 2013. JAMA Oncol 1:505–527. Scholar
  46. Fortunato A, Boddy A, Mallo D et al (2017) Natural selection in cancer biology: from molecular snowflakes to trait hallmarks. Cold Spring Harb Perspect Med 7:1–14. Scholar
  47. Fouad YA, Aanei C (2017) Revisiting the hallmarks of cancer. Am J Cancer Res 7:1016–1036PubMedPubMedCentralGoogle Scholar
  48. Gallaher JA, Enriquez-Navas PM, Luddy KA et al (2017) Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies. bioRxiv:1–21.
  49. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899. Scholar
  50. Gatenby RA, Smallbone K, Maini PK et al (2007) Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer 97:646–653. Scholar
  51. Gatenby RA, Silva AS, Gillies RJ, Frieden BR (2009) Adaptive therapy. Cancer Res 69:4894–4903. Scholar
  52. Gillies RJ, Verduzco D, Gatenby RA (2012) Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 12:487–493. Scholar
  53. Gonzalez H, Hagerling C, Werb Z (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev 32:1267–1284. Scholar
  54. Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481:306–313. Scholar
  55. Gu H, Huang T, Shen Y et al (2018) Reactive oxygen species-mediated tumor microenvironment transformation: the mechanism of radioresistant gastric Cancer. Oxidative Med Cell Longev 2018:1–8. Scholar
  56. Guillaumond F, Leca J, Olivares O et al (2013) Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci 110:3919–3924. Scholar
  57. Gupta S, Roy A, Dwarakanath BS (2017) Metabolic cooperation and competition in the tumor microenvironment: implications for therapy. Front Oncol 7:1–24. Scholar
  58. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322. Scholar
  59. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70. Scholar
  60. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. Scholar
  61. Hicks KC, Knudson KM, Jones FR, et al (2018, April 14–18) Abstract 1740: epigenetic reprogramming of the tumor microenvironment by entinostat increases tumor sensitivity to multivalent immunotherapy combinations with an IL-15 superagonist plus vaccine or immune checkpoint blockade. In: AACR annual meeting 2018. Chicago, p 1740Google Scholar
  62. Ibrahim-Hashim A, Gillies RJ, Brown JS, Gatenby RA (2017) Coevolution of tumor cells and their microenvironment: “niche construction in Cancer” In: Ujvari B, Roche B, Thomas F (eds) Ecology and evolution of cancer. Elsevier Inc., pp 111–117Google Scholar
  63. Jiménez-Sánchez A, Memon D, Pourpe S et al (2017) Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170:927–938.e20. Scholar
  64. Jo Y, Choi N, Kim K et al (2018) Chemoresistance of cancer cells: requirements of tumor microenvironment-mimicking in vitro models in anti-cancer drug development. Theranostics 8:5259–5275. Scholar
  65. Karpathiou G, Vieville M, Gavid M et al (2019) Prognostic significance of tumor budding, tumor-stroma ratio, cell nests size, and stroma type in laryngeal and pharyngeal squamous cell carcinomas. Head Neck 41:1918–1927. Scholar
  66. Kartal S (2014) Mathematical modeling and analysis of tumor-immune system interaction by using Lotka-Volterra predator-prey like model with piecewise constant arguments. Period Eng Nat Sci 2:7–12. Scholar
  67. Kaur G, Ahmad N (2014) On study of immune response to tumor cells in prey-predator system. Int Sch Res Not 2014:1–8. Scholar
  68. Kemi N, Eskuri M, Herva A et al (2018) Tumour-stroma ratio and prognosis in gastric adenocarcinoma. Br J Cancer 119:435–439. Scholar
  69. Korobeinikova A, Starkovc KE, Valle PA (2017) Modeling cancer evolution: evolutionary escape under immune system control. J Phys Conf Ser 811:012004–012012. Scholar
  70. Koshiji M, To KKW, Hammer S et al (2005) HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol Cell 17:793–803. Scholar
  71. Lacina L, Čoma M, Dvořánková B et al (2019) Evolution of Cancer progression in the context of Darwinism. Anticancer Res 39:1–16. Scholar
  72. Lambert AW, Pattabiraman DR, Weinberg RA (2017) Emerging biological principles of metastasis. Cell 168:670–691. Scholar
  73. Leong SP, Aktipis A, Maley C (2018) Cancer initiation and progression within the cancer microenvironment. Clin Exp Metastasis 35:361–367. Scholar
  74. Levayer R (2019) Solid stress, competition for space and cancer: the opposing roles of mechanical cell competition in tumour initiation and growth. Semin Cancer Biol:1–12.
  75. Li C, Little JB, Hu K (2001) Persistent genetic instability in Cancer cells induced by non-DNA-damaging stress exposures advances in brief persistent genetic instability in cancer cells induced by non-DNA-damaging. Cancer Res 61:428–432PubMedGoogle Scholar
  76. Liu J, Liu J, Li J et al (2014) Tumor–stroma ratio is an independent predictor for survival in early cervical carcinoma. Gynecol Oncol 132:81–86. Scholar
  77. Lopes-Coelho F, André S, Félix A, Serpa J (2018) Breast cancer metabolic cross-talk: fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol Cell Endocrinol 462:93–106. Scholar
  78. Lugini L, Matarrese P, Tinari A et al (2006) Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res 66:3629–3638. Scholar
  79. Luoto KR, Kumareswaran R, Bristow RG (2013) Tumor hypoxia as a driving force in genetic instability. Genome Integr 4:1–15. Scholar
  80. Lyssiotis CA, Kimmelman AC (2017) Metabolic interactions in the tumor microenvironment. Trends Cell Biol 27:863–875. Scholar
  81. Maacha S, Bhat AA, Jimenez L et al (2019) Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance. Mol Cancer 18:1–16. Scholar
  82. Maley CC, Aktipis A, Graham TA et al (2017) Classifying the evolutionary and ecological features of neoplasms. Nat Rev Cancer 17:605–619. Scholar
  83. Mansoori B, Mohammadi A, Davudian S et al (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7:339–348. Scholar
  84. Martín-Pardillos A, Valls-Chiva A, Serrano EB, et al (2018, April 14–18) Abstract 2183: clonal cooperation in cancer progression: a new paradigm in cancer. In: AACR annual meeting 2018. Chicago. p 2183Google Scholar
  85. Marullo R, Werner E, Degtyareva N et al (2013) Cisplatin induces a mitochondrial-ros response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One 8:1–15. Scholar
  86. McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168:613–628. Scholar
  87. Merlo LMF, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6:924–935. Scholar
  88. Miller BE, Miller FR, Wilburn D, Heppner GH (1988) Dominance of a tumor subpopulation line in mixed heterogeneous mouse mammary tumors. Cancer Res 48:5747–5753PubMedGoogle Scholar
  89. Milo I, Bedora-Faure M, Garcia Z et al (2018) The immune system profoundly restricts intratumor genetic heterogeneity. Sci Immunol 3:1–14. Scholar
  90. Nagraj J, Mukherjee S, Chowdhury R (2015) Cancer: an evolutionary perspective. J Cancer Biol Res 3:1064–1068Google Scholar
  91. Nakazawa MS, Keith B, Simon MC (2016) Oxygen availability and metabolic adaptations. Nat Rev Cancer 16:663–673. Scholar
  92. Niehr F, Eder T, Pilz T et al (2018) Multilayered omics-based analysis of a head and neck Cancer model of cisplatin resistance reveals intratumoral heterogeneity and treatment-induced clonal selection. Clin Cancer Res 24:158–168. Scholar
  93. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28. Scholar
  94. Odunsi K (2018) Abstract IA22: reprogramming the tumor microenvironment and T cells for ovarian cancer immunotherapy. In: AACR special conference: addressing critical questions in ovarian Cancer research and treatment; October 1-4, 2017; Pittsburgh, PA. p IA22Google Scholar
  95. Ovens K, Naugler C (2012) Preliminary evidence of different selection pressures on cancer cells as compared to normal tissues. Theor Biol Med Model 9:44–54. Scholar
  96. Paolicchi E, Gemignani F, Krstic-Demonacos M et al (2016) Targeting hypoxic response for cancer therapy. Oncotarget 7:13464–13478. Scholar
  97. Pellegrini P, Serviss JT, Lundbäck T et al (2018) A drug screening assay on cancer cells chronically adapted to acidosis. Cancer Cell Int 18:1–15. Scholar
  98. Pepper JW, Scott Findlay C, Kassen R et al (2009) Cancer research meets evolutionary biology. Evol Appl 2:62–70. Scholar
  99. Pillai SR, Damaghi M, Marunaka Y et al (2019) Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev 38:205–222. Scholar
  100. Pisarsky L, Bill R, Fagiani E et al (2016) Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15:1161–1174. Scholar
  101. Qian JJ, Akçay E (2018) Competition and niche construction in a model of cancer metastasis. PLoS One 13:1–20. Scholar
  102. Rankin EB, Giaccia AJ (2016) Hypoxic control of metastasis. Science 352:175–180. Scholar
  103. Reynolds TV, Rockwell S, Gazer PM (1996) Genetic instability induced by the tumor microenvironment. Cancer Res 56:5754–5757PubMedGoogle Scholar
  104. Riemann A, Reime S, Thews O (2017) Tumor acidosis and hypoxia differently modulate the inflammatory program: measurements in vitro and in vivo. Neoplasia 19:1033–1042. Scholar
  105. Roma-Rodrigues C, Mendes R, Baptista PV, Fernandes AR (2019) Targeting tumor microenvironment for cancer therapy. Int J Mol Sci 20:1–31. Scholar
  106. Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33:207–214. Scholar
  107. Senthebane DA, Rowe A, Thomford NE et al (2017) The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer. Int J Mol Sci 18:1–30. Scholar
  108. Senthebane DA, Jonker T, Rowe A et al (2018) The role of tumor microenvironment in chemoresistance: 3D extracellular matrices as accomplices. Int J Mol Sci 19:1–32. Scholar
  109. Son B, Lee S, Youn H et al (2017) The role of tumor microenvironment in therapeutic resistance. Oncotarget 8:3933–3945. Scholar
  110. Sun D, Dalin S, Hemann MT et al (2016) Differential selective pressure alters rate of drug resistance acquisition in heterogeneous tumor populations. Sci Rep 6:1–13. Scholar
  111. Tafani M, Sansone L, Limana F et al (2016) The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression. Oxidative Med Cell Longev 2016:1–18. Scholar
  112. Tang L, Wei F, Wu Y et al (2018) Role of metabolism in cancer cell radioresistance and radiosensitization methods. J Exp Clin Cancer Res 37:1–15. Scholar
  113. Toth RK, Warfel NA (2017) Strange bedfellows: nuclear factor, erythroid 2-like 2 (Nrf2) and hypoxia-inducible factor 1 (HIF-1) in tumor hypoxia. Antioxidants (Basel, Switzerland) 6:1–21. Scholar
  114. van Pelt GW, Kjær-Frifeldt S, van Krieken JHJM et al (2018) Scoring the tumor-stroma ratio in colon cancer: procedure and recommendations. Virchows Arch 473:405–412. Scholar
  115. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239. Scholar
  116. Venkatesan S, Swanton C, Taylor BS, Costello JF (2017) Treatment-induced mutagenesis and selective pressures sculpt cancer evolution. Cold Spring Harb Perspect Med 7:1–16. Scholar
  117. Wang k, Ma W, Wang J et al (2012) Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol 7:1457–1461. Scholar
  118. Wigerup C, Påhlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169. Scholar
  119. Wojtkowiak JW, Rothberg JM, Kumar V et al (2012) Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Res 72:3938–3947. Scholar
  120. Wu TS, Lin BR, Chang HH (2015) Radio resistance mechanisms of cancers: an overview and future perspectives. Biol Med s2:1–7. Scholar
  121. Yu Y, Cui J (2018) Present and future of cancer immunotherapy: a tumor microenvironmental perspective. Oncol Lett 16:4105–4113. Scholar
  122. Zhang X-L, Jiang C, Zhang Z-X et al (2014) The tumor-stroma ratio is an independent predictor for survival in nasopharyngeal cancer. Oncol Res Treat 37:480–484. Scholar
  123. Zhang J, Cunningham JJ, Brown JS, Gatenby RA (2017) Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat Commun 8:1–9. Scholar
  124. Zhou J, Schmid T, Schnitzer S, Brüne B (2006) Tumor hypoxia and cancer progression. Cancer Lett 237:10–21. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Sofia C. Nunes
    • 1
    • 2
  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

Personalised recommendations