Biology & Philosophy

, Volume 27, Issue 6, pp 785–810 | Cite as

Cancer cells and adaptive explanations

  • Pierre-Luc Germain


The aim of this paper is to assess the relevance of somatic evolution by natural selection to our understanding of cancer development. I do so in two steps. In the first part of the paper, I ask to what extent cancer cells meet the formal requirements for evolution by natural selection, relying on Godfrey-Smith’s (Darwinian populations and natural selection. Oxford University Press, Oxford, 2009) framework of Darwinian populations. I argue that although they meet the minimal requirements for natural selection, cancer cells are not paradigmatic Darwinian populations. In the second part of the paper, I examine the most important examples of adaptation in cancer cells. I argue that they are not significant accumulations of evolutionary changes, and that as a consequence natural selection plays a lesser role in their explanation. Their explanation, I argue, is best sought in the previously existing wiring of the healthy cells.


Cancer Adaptation Natural selection Explanation Darwinian populations 



I am particularly indebted to Mark A. Bedau and Fridolin Groß, who offered very precious assistance in this project, as well as to an anonymous reviewer who was particularly helpful. In addition, I would like to thank all those who took the time to read and comment any of the countless drafts of this paper: Giuseppe Testa, Michel Morange, Pierre-Olivier Méthot, Giovanni Boniolo, Marcel Weber, Lorenzo Del Savio, Annette Kappeler, Marco Annoni, Cecilia Nardini and Matteo Mamelli. Finally, I owe to the European School of Molecular Medicine (SEMM), the IFOM-IEO Campus and the FOLSATEC program the chance to have delved deeper into this science.


  1. Adams JM, Strasser A (2008) Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res 68:4018–4021. doi: 10.1158/0008-5472.CAN-07-6334 CrossRefGoogle Scholar
  2. Allegrucci C, Rushton MD, Dixon JE et al (2011) Epigenetic reprogramming of breast cancer cells with oocyte extracts. Molecular Cancer 10:7. doi: 10.1186/1476-4598-10-7 Google Scholar
  3. Anderson K, Lutz C, van Delft FW et al (2011) Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469:356–361. doi: 10.1038/nature09650 CrossRefGoogle Scholar
  4. Armitage P, Doll R (1957) A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer 11:161–169CrossRefGoogle Scholar
  5. Attolini CS-O, Michor F (2009) Evolutionary theory of cancer. Ann N Y Acad Sci 1168:23–51. doi: 10.1111/j.1749-6632.2009.04880.x CrossRefGoogle Scholar
  6. Bailar JC, Smith EM (1986) Progress against cancer? N Engl J Med 314:1226–1232. doi: 10.1056/NEJM198605083141905 CrossRefGoogle Scholar
  7. Bailey CM, Morrison J, Kulesa PM (2012) Melanoma revives an embryonic migration program to promote plasticity and invasion. Pigment Cell & Melanoma Research. doi: 10.1111/j.1755-148X.2012.01025.x Google Scholar
  8. Barker N, Ridgway RA, van Es JH et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–611. doi: 10.1038/nature07602 CrossRefGoogle Scholar
  9. Beckman RA, Loeb LA (2006) Efficiency of carcinogenesis with and without a mutator mutation. Proc Nat Acad Sci 103:14140–14145. doi: 10.1073/pnas.0606271103 CrossRefGoogle Scholar
  10. Belov K (2012) Contagious cancer: lessons from the devil and the dog. BioEssays 34:285–292. doi: 10.1002/bies.201100161 CrossRefGoogle Scholar
  11. Bertolaso M (2011) Hierarchies and causal relationships in interpretative models of the neoplastic process. Hist Philos Life Sci 33:515–5138Google Scholar
  12. Bhowmick N, Neilson E (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337CrossRefGoogle Scholar
  13. Bhowmick N, Chytil A, Plieth D et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851. doi: 10.1126/science.1090922 CrossRefGoogle Scholar
  14. Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1:46–54. doi: 10.1038/35094059 CrossRefGoogle Scholar
  15. Bouchard F (2008) Causal processes, fitness, and the differential persistence of lineages. Philosophy of Science 75(5):560–570. doi: 10.1086/594507 CrossRefGoogle Scholar
  16. Boudreau N, Sympson CJ, Werb Z, Bissell MJ (1995) Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267:891–893CrossRefGoogle Scholar
  17. Buss LW (1987) The evolution of individuality. Princeton University Press, PrincetonGoogle Scholar
  18. Bussard KM, Boulanger Ca, Booth BW et al (2010) Reprogramming human cancer cells in the mouse mammary gland. Cancer Res 70:6336–6343. doi: 10.1158/0008-5472.CAN-10-0591 CrossRefGoogle Scholar
  19. Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255:197–200CrossRefGoogle Scholar
  20. Colosimo PF, Peichel CL, Nereng K et al (2004) The genetic architecture of parallel armor plate reduction in threespine sticklebacks. PLoS Biol 2:E109. doi: 10.1371/journal.pbio.0020109 CrossRefGoogle Scholar
  21. Colosimo PF, Hosemann KE, Balabhadra S et al (2005) Widespread parallel evolution in sticklebacks by repeated fixation of ectodysplasin alleles. Science 307:1928–1933. doi: 10.1126/science.1107239 CrossRefGoogle Scholar
  22. Corada M, Zanetta L, Orsenigo F et al (2002) A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood 100:905–911CrossRefGoogle Scholar
  23. De Vries A, Flores ER, Miranda B et al (2002) Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Nat Acad Sci 99:2948–2953CrossRefGoogle Scholar
  24. Dick JE (2003) Breast cancer stem cells revealed. Proc Natl Acad Sci 100(7):3547–3549. doi: 10.1073/pnas.0830967100 Google Scholar
  25. Eheman C, Henley S, Ballard-Barbash R (2012) Annual report to the nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. doi: 10.1002/cncr.27514
  26. Frank SA (2007) Dynamics of cancer: incidence, inheritance, and evolution. Princeton University Press, PrincetonGoogle Scholar
  27. Frank SA, Nowak MA (2004) Problems of somatic mutation and cancer. BioEssays 26(3):291–299. doi: 10.1002/bies.20000 Google Scholar
  28. Frank SA, Iwasa Y, Nowak MA (2003) Patterns of cell division and the risk of cancer. Genetics 163:1527–1532Google Scholar
  29. Frank NY, Schatton T, Frank MH (2010) The therapeutic promise of the cancer stem cell concept. Journal of Clinical Investigation 120:41–50CrossRefGoogle Scholar
  30. Gardner RL (1975) Fate of teratocarcinoma cells injected into early mouse embryos. Nature 258:70CrossRefGoogle Scholar
  31. Gatenby RA, Gillies RJ (2008) A microenvironmental model of carcinogenesis. Nat Rev Cancer 8:56–61. doi: 10.1038/nrc2255 CrossRefGoogle Scholar
  32. Gerlinger M, Swanton C (2010) How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br J Cancer 103:1139–1143. doi: 10.1038/sj.bjc.6605912 CrossRefGoogle Scholar
  33. Gillies RJ, Verduzco D, Gatenby Ra (2012) Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 12:487–493. doi: 10.1038/nrc3298 CrossRefGoogle Scholar
  34. Godfrey-Smith P (2009) Darwinian populations and natural selection. Oxford University Press, OxfordGoogle Scholar
  35. Goldie JH, Coldman AJ (1984) The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res 44:3643–3653Google Scholar
  36. Gould SJ, Lewontin RC (1979) The Spandrels of San Marco and the Panglossian Paradigm: a critique of the adaptationist programme. Proc R Soc Lond B 205:581–598CrossRefGoogle Scholar
  37. Gregory CD, Pound JD (2011) Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J Pathol 223:177–194. doi: 10.1002/path.2792 CrossRefGoogle Scholar
  38. Grompe M (2012) Tissue stem cells: new tools and functional diversity. Cell Stem Cell 10:685–689. doi: 10.1016/j.stem.2012.04.006 CrossRefGoogle Scholar
  39. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefGoogle Scholar
  40. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi: 10.1016/j.cell.2011.02.013 CrossRefGoogle Scholar
  41. Heng HHQ, Stevens JB, Bremer SW et al (2010) The evolutionary mechanism of cancer. J Cell Biochem 109:1072–1084. doi: 10.1002/jcb.22497 Google Scholar
  42. Hochedlinger K, Blelloch R, Brennan C et al (2004) Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev 18:1875–1885. doi: 10.1101/gad.1213504 CrossRefGoogle Scholar
  43. Huang S (2011) On the intrinsic inevitability of cancer: from foetal to fatal attraction. Semin Cancer Biol 21:183–199. doi: 10.1016/j.semcancer.2011.05.003 CrossRefGoogle Scholar
  44. Hull DL, Langman RE, Glenn SS (2001) A general account of selection: biology, immunology, and behavior. The Behavioral and brain sciences 24:511–528CrossRefGoogle Scholar
  45. Kai T, Spradling A (2004) Differentiating germ cells can revert into functional stem cells in drosophila melanogaster ovaries. Nature 428:564–569CrossRefGoogle Scholar
  46. Khong H (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 3:999–1005CrossRefGoogle Scholar
  47. Kingsley DM, Peichel CL (2007) The molecular genetics of evolutionary change in sticklebacks. Biology of the threespine stickleback. CRC Press, Boca Raton, pp 4–81Google Scholar
  48. Kolata G (1999) Clone: the road to dolly and the path ahead. Harper PerennialGoogle Scholar
  49. Leroi AM, Koufopanou V, Burt A (2003) Cancer selection. Nat Rev Cancer 3:226–231. doi: 10.1038/nrc1016 CrossRefGoogle Scholar
  50. Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079Google Scholar
  51. Maenhaut C, Dumont JE, Roger PP, Van Staveren WCG (2010) Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? an analysis. Carcinogenesis 31:149–158CrossRefGoogle Scholar
  52. Maley CC, Galipeau PC, Finley JC et al (2006) Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet 38:468–473. doi: 10.1038/ng1768 CrossRefGoogle Scholar
  53. Merlo LMF, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6:924–935. doi: 10.1038/nrc2013 CrossRefGoogle Scholar
  54. Miller SJ, Lavker RM, Sun T-T (2005) Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications. Biochim Biophys Acta 1756:25–52. doi: 10.1016/j.bbcan.2005.07.003 Google Scholar
  55. Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Nat Acad Sci USA 72:3585–3589CrossRefGoogle Scholar
  56. Nik-Zainal S, Alexandrov LB, Wedge DC, et al. (2012) Mutational processes molding the genomes of 21 breast cancers. Cell 979–993. doi: 10.1016/j.cell.2012.04.024
  57. Nik-Zainal S, Van Loo P, Wedge DC et al (2012b) The life history of 21 breast cancers. Cell. doi: 10.1016/j.cell.2012.04.023 Google Scholar
  58. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28. doi: 10.1126/science.959840 CrossRefGoogle Scholar
  59. Pece S, Tosoni D, Confalonieri S et al (2010) Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140:62–73. doi: 10.1016/j.cell.2009.12.007 CrossRefGoogle Scholar
  60. Pepper JW, Findlay CS, Kassen R et al (2009) Cancer research meets evolutionary biology. Evol Appl 2:62–70. doi: 10.1111/j.1752-4571.2008.00063.x CrossRefGoogle Scholar
  61. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480(7377):1–5. doi: 10.1038/nature10662 Google Scholar
  62. Rabinovitch PS, Reid BJ, Haggitt RC, Norwood TH, Rubin CE (1989) Progression to cancer in Barrett’s esophagus is associated with genomic instability. Lab Invest 60:65–71Google Scholar
  63. Ridley M (2007) Evolution, 3rd edn. Blackwell, OxfordGoogle Scholar
  64. Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N et al (2002) Several types of mutations of the abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100:1014–1018CrossRefGoogle Scholar
  65. Rubin H (2006) What keeps cells in tissues behaving normally in the face of myriad mutations? BioEssays 28:515–524. doi: 10.1002/bies.20403 CrossRefGoogle Scholar
  66. Sabatino M, Zhao Y, Voiculescu S et al (2008) Conservation of genetic alterations in recurrent melanoma supports the melanoma stem cell hypothesis. Cancer Res 68:122–131CrossRefGoogle Scholar
  67. Shibata D (2006) Clonal diversity in tumor progression. Nat Genet 38:402–403. doi: 10.1038/ng0406-402 CrossRefGoogle Scholar
  68. Singer T, McConnell MJ, Marchetto MCN et al (2010) LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci 33:345–354CrossRefGoogle Scholar
  69. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751. doi: 10.1038/onc.2010.215 CrossRefGoogle Scholar
  70. Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828. doi: 10.1038/nature03128 Google Scholar
  71. Smalley KSM, Herlyn M (2009) Integrating tumor-initiating cells into the paradigm for melanoma targeted therapy. Int J Cancer 124:1245–1250. doi: 10.1002/ijc.24129 CrossRefGoogle Scholar
  72. Soto AM, Sonnenschein C (2004) The somatic mutation theory of cancer: growing problems with the paradigm? BioEssays 26:1097–1107. doi: 10.1002/bies.20087 CrossRefGoogle Scholar
  73. Srivastava S, Wang S, Tong YA, Hao ZM, Chang EH (1993) Dominant negative effect of a germ-line mutant p53: a step fostering tumorigenesis. Cancer Res 53(19):4452–4455Google Scholar
  74. Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40. doi: 10.1016/j.cell.2010.11.055 CrossRefGoogle Scholar
  75. Sterelny K (2006) The evolution and evolvability of culture. Mind & language 21(2):137–165. doi: 10.1111/j.0268-1064.2006.00309.x CrossRefGoogle Scholar
  76. Sterelny K (2007) What is evolvability? In: Matthen M, Stephens C (eds) The Elsevier handbook of the philosophy of biology. Elsevier, Amsterdam, pp 163–178Google Scholar
  77. Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 331:1553–1558. doi: 10.1126/science.1204040 CrossRefGoogle Scholar
  78. Straussman R, Morikawa T, Shee K et al (2012) Tumour micro-environment elicits innate resistance to raf inhibitors through HGF secretion. Nature. doi: 10.1038/nature11183 Google Scholar
  79. Visvader JE, Lindeman GJ (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10:717–728. doi: 10.1016/j.stem.2012.05.007 CrossRefGoogle Scholar
  80. Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141CrossRefGoogle Scholar
  81. Voog J, Jones DL (2010) Stem cells and the niche: a dynamic duo. Cell Stem Cell 6:103–115CrossRefGoogle Scholar
  82. Waters CK (2007) Causes that make a difference. J Philos 104(11):551–579Google Scholar
  83. Ye CJ, Stevens JB, Liu G et al (2009) Genome based cell population heterogeneity promotes tumorigenicity: the evolutionary mechanism of cancer. J Cell Physiol 219:288–300. doi: 10.1002/jcp.21663 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Università degli Studi di Milano, European Institute of Oncology (IEO)MilanItaly

Personalised recommendations