Skip to main content
SpringerLink
Log in

How Do Mutant Clones Expand in Normal Tissue?

  • Chapter
  • First Online:
Frontiers in Cancer Research

  • 612 Accesses

Abstract

Normal tissue in human skin, breast, lung, colon, pancreas, and blood contains clones of mutant cells, often at high frequency. These seem to be early stages in cancer development. Clonal expansion from a single mutant cell appears to be driven by physiological events affecting the entire tissue, rather than by the mutant cell acquiring an additional mutation that triggers “uncontrolled proliferation”. In epithelial tissue, these physiological events include apoptosis and stem-cell fate decisions, which act as selection pressures favoring the mutant cell. These events create incubators for genetic variation and guide the course of tumor evolution.

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. Cha RS, Thilly WG, Zarbl H (1994) N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. Proc Natl Acad Sci U S A 91:3749–3753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nakazawa H, English D, Randell PL, Nakazawa K, Martel N, Armstrong BK, Yamasaki H (1994) UV and skin cancer: specific p53 gene mutation in normal skin as a biologically relevant exposure measurement. Proc Natl Acad Sci U S A 91:360–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–776

    Article  CAS  PubMed  Google Scholar 

  4. Busuttil RA, Garcia AM, Reddick RL, Dolle ME, Calder RB, Nelson JF, Vijg J (2007) Intra-organ variation in age-related mutation accumulation in the mouse. PLoS One 2(9), e876. doi:10.1371/journal.pone.0000876

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Bean GR, Bryson AD, Pilie PG, Goldenberg V, Baker JC Jr, Ibarra C, Brander DM, Paisie C, Case NR, Gauthier M, Reynolds PA, Dietze E, Ostrander J, Scott V, Wilke LG, Yee L, Kimler BF, Fabian CJ, Zalles CM, Broadwater G, Tlsty TD, Seewaldt VL (2007) Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF. Clin Cancer Res 13(22 Pt 1):6834–6841

    Article  CAS  PubMed  Google Scholar 

  6. Moore MR, Drinkwater NR, Miller EC, Miller JA, Pitot HC (1981) Quantitative analysis of the time-dependent development of glucose-6-phosphatase-deficient foci in the livers of mice treated neonatally with diethylnitrosamine. Cancer Res 41(5):1585–1593

    CAS  PubMed  Google Scholar 

  7. Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE, Brash DE (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci U S A 93:14025–14029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ren ZP, Ponten F, Nister M, Ponten J (1996) Two distinct p53 immunohistochemical patterns in human squamous cell skin cancer, precursors, and normal epidermis. Int J Cancer 69:174–179

    Article  CAS  PubMed  Google Scholar 

  9. Berg RJ, van Kranen HJ, Rebel HG, de Vries A, van Vloten WA, Van Kreijl CF, van der Leun JC, de Gruijl FR (1996) Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells. Proc Natl Acad Sci U S A 93(1):274–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang W, Remenyik E, Zelterman D, Brash DE, Wikonkal NM (2001) Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. Proc Natl Acad Sci U S A 98:13948–13953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brash DE (2015) UV signature mutations. Photochem Photobiol 91:15–26

    Article  CAS  PubMed  Google Scholar 

  12. Rebel H, Mosnier LO, Berg RJW, Westeman-de Vires A, Steeg H, van Kranen HJ, de Gruijl F (2001) Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity. Cancer Res 61:977–983

    CAS  PubMed  Google Scholar 

  13. Rebel H, Kram N, Westerman A, Banus S, van Kranen HJ, de Gruijl FR (2005) Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice. Carcinogenesis 26(12):2123–2130

    Article  CAS  PubMed  Google Scholar 

  14. Rebel HG, Bodmann CA, van de Glind GC, de Gruijl FR (2012) UV-induced ablation of the epidermal basal layer including p53-mutant clones resets UV carcinogenesis showing squamous cell carcinomas to originate from interfollicular epidermis. Carcinogenesis 33(3):714–720

    Article  CAS  PubMed  Google Scholar 

  15. McDonald SA, Preston SL, Greaves LC, Leedham SJ, Lovell MA, Jankowski JA, Turnbull DM, Wright NA (2006) Clonal expansion in the human gut: mitochondrial DNA mutations show us the way. Cell Cycle 5(8):808–811

    Article  CAS  PubMed  Google Scholar 

  16. McDonald SA, Greaves LC, Gutierrez-Gonzalez L, Rodriguez-Justo M, Deheragoda M, Leedham SJ, Taylor RW, Lee CY, Preston SL, Lovell M, Hunt T, Elia G, Oukrif D, Harrison R, Novelli MR, Mitchell I, Stoker DL, Turnbull DM, Jankowski JA, Wright NA (2008) Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134(2):500–510

    Article  CAS  PubMed  Google Scholar 

  17. Park HS, Goodlad RA, Wright NA (1995) Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens. Am J Pathol 147(5):1416–1427

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wiktor-Brown DM, Olipitz W, Hendricks CA, Rugo RE, Engelward BP (2008) Tissue-specific differences in the accumulation of sequence rearrangements with age. DNA Repair (Amst) 7(5):694–703

    Article  CAS  Google Scholar 

  19. Wiktor-Brown DM, Kwon HS, Nam YS, So PT, Engelward BP (2008) Integrated one- and two-photon imaging platform reveals clonal expansion as a major driver of mutation load. Proc Natl Acad Sci U S A 105(30):10314–10319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Muzumdar MD, Luo L, Zong H (2007) Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM). Proc Natl Acad Sci U S A 104(11):4495–4500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu M, Pastor-Pareja JC, Xu T (2010) Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463(7280):545–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gonzalez-Garcia I, Sole RV, Costa J (2002) Metapopulation dynamics and spatial heterogeneity in cancer. Proc Natl Acad Sci U S A 99(20):13085–13089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brentnall TA, Crispin DA, Rabinovitch, PS, Haggitt RC, Rubin CE, Stevens AC, Burmer GC (1994) Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 107:369–378

    Google Scholar 

  24. Leedham SJ, Graham TA, Oukrif D, McDonald SA, Rodriguez-Justo M, Harrison RF, Shepherd NA, Novelli MR, Jankowski JA, Wright NA (2009) Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology 136(2):542–550

    Article  PubMed  Google Scholar 

  25. Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG, Rabinovitch PS, Reid BJ (1999) Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 22(1):106–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prevo LJ, Sanchez CA, Galipeau PC, Reid BJ (1999) p53-mutant clones and field effects in Barrett’s esophagus. Cancer Res 59(19):4784–4787

    CAS  PubMed  Google Scholar 

  27. Maley CC, Galipeau PC, Li X, Sanchez CA, Paulson TG, Reid BJ (2004) Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett’s esophagus. Cancer Res 64(10):3414–3427

    Article  CAS  PubMed  Google Scholar 

  28. Maley CC, Galipeau PC, Li X, Sanchez CA, Paulson TG, Blount PL, Reid BJ (2004) The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res 64(20):7629–7633

    Article  CAS  PubMed  Google Scholar 

  29. Sudo H, Li-Sucholeiki XC, Marcelino LA, Gruhl AN, Herrero-Jimenez P, Zarbl H, Willey JC, Furth EE, Morgenthaler S, Coller HA, Ekstrom PO, Kurzweil R, Gostjeva EV, Thilly WG (2008) Fetal-juvenile origins of point mutations in the adult human tracheal-bronchial epithelium: absence of detectable effects of age, gender or smoking status. Mutat Res 646(1-2):25–40

    Article  CAS  PubMed  Google Scholar 

  30. Franklin WA, Gazdar AF, Haney J, Wistuba II, La Rosa FG, Kennedy T, Ritchey DM, Miller YE (1997) Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J Clin Invest 100:2133–2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274(5295):2057–2059

    Article  CAS  PubMed  Google Scholar 

  32. Park IW, Wistuba II, Maitra A, Milchgrub S, Virmani AK, Minna JD, Gazdar AF (1999) Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer. J Natl Cancer Inst 91(21):1863–1868

    Article  CAS  PubMed  Google Scholar 

  33. Tabor MP, Brakenhoff RH, van Houten VM, Kummer JA, Snel MH, Snijders PJ, Snow GB, Leemans CR, Braakhuis BJ (2001) Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 7(6):1523–1532

    CAS  PubMed  Google Scholar 

  34. Majewski T, Lee S, Jeong J, Yoon DS, Kram A, Kim MS, Tuziak T, Bondaruk J, Lee S, Park WS, Tang KS, Chung W, Shen L, Ahmed SS, Johnston DA, Grossman HB, Dinney CP, Zhou JH, Harris RA, Snyder C, Filipek S, Narod SA, Watson P, Lynch HT, Gazdar A, Bar-Eli M, Wu XF, McConkey DJ, Baggerly K, Issa JP, Benedict WF, Scherer SE, Czerniak B (2008) Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy. Lab Invest 88(7):694–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gailani MR, Bale SJ, Leffell DJ, DiGiovanna JJ, Peck GL, Poliak S, Drum MA, Pastakia B, McBride OW, Kase R, Greene M, Mulvihill JJ, Bale AE (1992) Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell 69:111–117

    Article  CAS  PubMed  Google Scholar 

  36. Levanat S, Gorlin RJ, Fallet S, Johnson DR, Fantasia JE, Bale AE (1996) A two-hit model for developmental defects in Gorlin syndrome. Nat Genet 12:85–87

    Article  CAS  PubMed  Google Scholar 

  37. Barreto DC, Gomez RS, Bale AE, Boson WL, De Marco L (2000) PTCH gene mutations in odontogenic keratocysts. J Dent Res 79(6):1418–1422

    Article  CAS  PubMed  Google Scholar 

  38. Gauthier ML, Berman HK, Miller C, Kozakeiwicz K, Chew K, Moore D, Rabban J, Chen YY, Kerlikowske K, Tlsty TD (2007) Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. Cancer Cell 12(5):479–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Recio L, Cochrane J, Simpson D, Skopek TR, O’Neill JP, Nicklas JA, Albertini RJ (1990) DNA sequence analysis of in vivo hprt mutation in human T lymphocytes. Mutagenesis 5(5):505–510

    Article  CAS  PubMed  Google Scholar 

  40. Finette BA, Homans AC, Rivers J, Messier T, Albertini RJ (2001) Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia. Leukemia 15(12):1898–1905

    Article  CAS  PubMed  Google Scholar 

  41. Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, Ferrandino AF, Rosenberg Belmaker LA, Szekely A, Wilson M, Kocabas A, Calixto NE, Grigorenko EL, Huttner A, Chawarska K, Weissman S, Urban AE, Gerstein M, Vaccarino FM (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492(7429):438–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, Ling H, Hetrick KN, Pugh EW, Amos C, Wei Q, Wang LE, Lee JE, Barnes KC, Hansel NN, Mathias R, Daley D, Beaty TH, Scott AF, Ruczinski I, Scharpf RB, Bierut LJ, Hartz SM, Landi MT, Freedman ND, Goldin LR, Ginsburg D, Li J, Desch KC, Strom SS, Blot WJ, Signorello LB, Ingles SA, Chanock SJ, Berndt SI, Le Marchand L, Henderson BE, Monroe KR, Heit JA, de Andrade M, Armasu SM, Regnier C, Lowe WL, Hayes MG, Marazita ML, Feingold E, Murray JC, Melbye M, Feenstra B, Kang JH, Wiggs JL, Jarvik GP, McDavid AN, Seshan VE, Mirel DB, Crenshaw A, Sharopova N, Wise A, Shen J, Crosslin DR, Levine DM, Zheng X, Udren JI, Bennett S, Nelson SC, Gogarten SM, Conomos MP, Heagerty P, Manolio T, Pasquale LR, Haiman CA, Caporaso N, Weir BS (2012) Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 44(6):642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, Hutchinson A, Deng X, Liu C, Horner MJ, Cullen M, Epstein CG, Burdett L, Dean MC, Chatterjee N, Sampson J, Chung CC, Kovaks J, Gapstur SM, Stevens VL, Teras LT, Gaudet MM, Albanes D, Weinstein SJ, Virtamo J, Taylor PR, Freedman ND, Abnet CC, Goldstein AM, Hu N, Yu K, Yuan JM, Liao L, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Aldrich MC, Amos C, Blot WJ, Bock CH, Gillanders EM, Harris CC, Haiman CA, Henderson BE, Kolonel LN, Le Marchand L, McNeill LH, Rybicki BA, Schwartz AG, Signorello LB, Spitz MR, Wiencke JK, Wrensch M, Wu X, Zanetti KA, Ziegler RG, Figueroa JD, Garcia-Closas M, Malats N, Marenne G, Prokunina-Olsson L, Baris D, Schwenn M, Johnson A, Landi MT, Goldin L, Consonni D, Bertazzi PA, Rotunno M, Rajaraman P, Andersson U, Beane Freeman LE, Berg CD, Buring JE, Butler MA, Carreon T, Feychting M, Ahlbom A, Gaziano JM, Giles GG, Hallmans G, Hankinson SE, Hartge P, Henriksson R, Inskip PD, Johansen C, Landgren A, McKean-Cowdin R, Michaud DS, Melin BS, Peters U, Ruder AM, Sesso HD, Severi G, Shu XO, Visvanathan K, White E, Wolk A, Zeleniuch-Jacquotte A, Zheng W, Silverman DT, Kogevinas M, Gonzalez JR, Villa O, Li D, Duell EJ, Risch HA, Olson SH, Kooperberg C, Wolpin BM, Jiao L, Hassan M, Wheeler W, Arslan AA, Bueno-de-Mesquita HB, Fuchs CS, Gallinger S, Gross MD, Holly EA, Klein AP, LaCroix A, Mandelson MT, Petersen G, Boutron-Ruault MC, Bracci PM, Canzian F, Chang K, Cotterchio M, Giovannucci EL, Goggins M, Hoffman Bolton JA, Jenab M, Khaw KT, Krogh V, Kurtz RC, McWilliams RR, Mendelsohn JB, Rabe KG, Riboli E, Tjonneland A, Tobias GS, Trichopoulos D, Elena JW, Yu H, Amundadottir L, Stolzenberg-Solomon RZ, Kraft P, Schumacher F, Stram D, Savage SA, Mirabello L, Andrulis IL, Wunder JS, Patino Garcia A, Sierrasesumaga L, Barkauskas DA, Gorlick RG, Purdue M, Chow WH, Moore LE, Schwartz KL, Davis FG, Hsing AW, Berndt SI, Black A, Wentzensen N, Brinton LA, Lissowska J, Peplonska B, McGlynn KA, Cook MB, Graubard BI, Kratz CP, Greene MH, Erickson RL, Hunter DJ, Thomas G, Hoover RN, Real FX, Fraumeni JF Jr, Caporaso NE, Tucker M, Rothman N, Perez-Jurado LA, Chanock SJ (2012) Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet 44(6):651–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH, Campbell PJ (2015) High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348(6237):880–886

    Google Scholar 

  45. Levy V, Lindon C, Harfe BD, Morgan BA (2005) Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell 9(6):855–861

    Article  CAS  PubMed  Google Scholar 

  46. Silva-Vargas V, Lo Celso C, Giangreco A, Ofstad T, Prowse DM, Braun KM, Watt FM (2005) Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev Cell 9(1):121–131

    Article  CAS  PubMed  Google Scholar 

  47. Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, Cotsarelis G (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11(12):1351–1354

    Article  CAS  PubMed  Google Scholar 

  48. Greco V, Chen T, Rendl M, Schober M, Pasolli HA, Stokes N, Dela Cruz-Racelis J, Fuchs E (2009) A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell 4(2):155–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Potten CS, Morris RJ (1988) Epithelial stem cells in vivo. In: Lord BI, Dexter TM (eds) Stem cells, vol 10. J Cell Sci Suppl. Company of Biologists Ltd, Cambridge, pp 45–62

    Google Scholar 

  50. Ghazizadeh S, Taichman LB (2001) Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J 20(6):1215–1222. doi:10.1093/emboj/20.6.1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mannik J, Alzayady K, Ghazizadeh S (2010) Regeneration of multilineage skin epithelia by differentiated keratinocytes. J Invest Dermatol 130(2):388–397

    Article  CAS  PubMed  Google Scholar 

  52. Clayton E, Doupe DP, Klein AM, Winton DJ, Simons BD, Jones PH (2007) A single type of progenitor cell maintains normal epidermis. Nature 446(7132):185–189

    Article  CAS  PubMed  Google Scholar 

  53. Doupe DP, Klein AM, Simons BD, Jones PH (2010) The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev Cell 18(2):317–323

    Article  CAS  PubMed  Google Scholar 

  54. Klein AM, Nakagawa T, Ichikawa R, Yoshida S, Simons BD (2010) Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7(2):214–224

    Article  CAS  PubMed  Google Scholar 

  55. Klein AM, Simons BD (2011) Universal patterns of stem cell fate in cycling adult tissues. Development 138(15):3103–3111

    Article  CAS  PubMed  Google Scholar 

  56. Mascre G, Dekoninck S, Drogat B, Youssef KK, Brohee S, Sotiropoulou PA, Simons BD, Blanpain C (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489(7415):257–262

    Article  CAS  PubMed  Google Scholar 

  57. Lopez-Garcia C, Klein AM, Simons BD, Winton DJ (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330(6005):822–825

    Article  CAS  PubMed  Google Scholar 

  58. Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143(1):134–144

    Article  CAS  PubMed  Google Scholar 

  59. Doupe DP, Alcolea MP, Roshan A, Zhang G, Klein AM, Simons BD, Jones PH (2012) A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337(6098):1091–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ousset M, Van Keymeulen A, Bouvencourt G, Sharma N, Achouri Y, Simons BD, Blanpain C (2012) Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat Cell Biol 14(11):1131–1138

    Article  CAS  PubMed  Google Scholar 

  61. Sherley JL, Stadler PB, Johnson DR (1995) Expression of the wild-type p53 antioncogene induces guanine nucleotide-dependent stem cell division kinetics. Proc Natl Acad Sci U S A 92:136–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sherr CJ (2001) The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2:731–737

    Google Scholar 

  63. Sherr CJ and McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2:103–112.

    Google Scholar 

  64. Wasan HS, Park HS, Liu KC, Mandir NK, Winnett A, Sasieni P, Bodmer WF, Goodlad RA, Wright NA (1998) APC in the regulation of intestinal crypt fission. J Pathol 185(3):246–255

    Article  CAS  PubMed  Google Scholar 

  65. Park HS, Goodlad RA, Ahnen DJ, Winnett A, Sasieni P, Lee CY, Wright NA (1997) Effects of epidermal growth factor and dimethylhydrazine on crypt size, cell proliferation, and crypt fission in the rat colon. Cell proliferation and crypt fission are controlled independently. Am J Pathol 151(3):843–852

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen R, Rabinovitch PS, Crispin DA, Emond MJ, Bronner MP, Brentnall TA (2005) The initiation of colon cancer in a chronic inflammatory setting. Carcinogenesis 26(9):1513–1519

    Article  CAS  PubMed  Google Scholar 

  67. Graeber TG, Osmanian C, Jacks T, Houseman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 379:88–91

    Article  CAS  PubMed  Google Scholar 

  68. Zhang W, Hanks AN, Florell SR, Allen SM, Alexander A, Boucher K, Brash DE, Grossman D (2005) UV-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 26:249–257

    Article  CAS  PubMed  Google Scholar 

  69. Chao DL, Eck JT, Brash DE, Maley CC, Luebeck EG (2008) Preneoplastic lesion growth driven by the death of adjacent normal stem cells. Proc Natl Acad Sci U S A 105(39):15034–15039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Klein A, Brash D, Jones P, Simons B (2010) Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UVB during preneoplasia. Proc Natl Acad Sci U S A 107:270–275

    Article  CAS  PubMed  Google Scholar 

  71. Brash D, Cairns J (2009) The mysterious steps in carcinogenesis. Br J Cancer 101(3):379–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Javaherian A, Vaccariello M, Fusenig NE, Garlick JA (1998) Normal keratinocytes suppress early stages of neoplastic progression in stratified epithelium. Cancer Res 15:2200–2208

    Google Scholar 

  73. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28

    Article  CAS  PubMed  Google Scholar 

  74. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata D, Curtis C (2015) A Big Bang model of human colorectal tumor growth. Nat Genet 47(3):209–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lyons JG, Siew K, O’Grady RL (1989) Cellular interactions determining the production of collagenase by a rat mammary carcinoma cell line. Int J Cancer 43(1):119–125

    Article  CAS  PubMed  Google Scholar 

  77. Martorana AM, Zheng G, Crowe TC, O’Grady RL, Lyons JG (1998) Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. Cancer Res 58(21):4970–4979

    CAS  PubMed  Google Scholar 

  78. Lyons JG, Lobo E, Martorana AM, Myerscough MR (2008) Clonal diversity in carcinomas: its implications for tumour progression and the contribution made to it by epithelial-mesenchymal transitions. Clin Exp Metastasis 25(6):665–677

    Article  PubMed  Google Scholar 

  79. Axelrod R, Axelrod DE, Pienta KJ (2006) Evolution of cooperation among tumor cells. Proc Natl Acad Sci U S A 103(36):13474–13479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Brumby AM, Richardson HE (2003) scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J 22(21):5769–5779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I, Devgan V, Lieb J, Raffoul W, Hohl D, Neel V, Garlick J, Chiorino G, Dotto GP (2007) Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev 21(5):562–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W, Proby CM, Leigh IM, Collisson EA, Gordon PB, Jakkula L, Pennypacker S, Zou Y, Sharma M, North JP, Vemula SS, Mauro TM, Neuhaus IM, Leboit PE, Hur JS, Park K, Huh N, Kwok PY, Arron ST, Massion PP, Bale AE, Haussler D, Cleaver JE, Gray JW, Spellman PT, South AP, Aster JC, Blacklow SC, Cho RJ (2011) Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci U S A 108(43):17761–17766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Khare A, Shaulsky G (2006) First among equals: competition between genetically identical cells. Nat Rev Genet 7(7):577–583

    Article  CAS  PubMed  Google Scholar 

  84. Moreno E (2008) Is cell competition relevant to cancer? Nat Rev Cancer 8(2):141–147

    Article  CAS  PubMed  Google Scholar 

  85. Rhiner C, Lopez-Gay JM, Soldini D, Casas-Tinto S, Martin FA, Lombardia L, Moreno E (2010) Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Dev Cell 18(6):985–998

    Article  CAS  PubMed  Google Scholar 

  86. Petrova E, Lopez-Gay JM, Rhiner C, Moreno E (2012) Flower-deficient mice have reduced susceptibility to skin papilloma formation. Dis Model Mech 5(4):553–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bondar T, Medzhitov R (2010) p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6(4):309–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Marusyk A, Porter CC, Zaberezhnyy V, DeGregori J (2010) Irradiation selects for p53-deficient hematopoietic progenitors. PLoS Biol 8(3), e1000324. doi:10.1371/journal.pbio.1000324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Marusyk A, Casas-Selves M, Henry CJ, Zaberezhnyy V, Klawitter J, Christians U, DeGregori J (2009) Irradiation alters selection for oncogenic mutations in hematopoietic progenitors. Cancer Res 69(18):7262–7269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cairns J (2011) The possible prevention of cancer. Environ Health 10(Suppl 1):S13

    Article  PubMed  PubMed Central  Google Scholar 

  91. Visvader JE, Lindeman GJ (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10(6):717–728

    Article  CAS  PubMed  Google Scholar 

  92. Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, Foreman O, Bronson RT, Nishiyama A, Luo L, Zong H (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146(2):209–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, Clevers H (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337(6095):730–735

    Article  CAS  PubMed  Google Scholar 

  94. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C (2012) Defining the mode of tumour growth by clonal analysis. Nature 488(7412):527–530

    Article  CAS  PubMed  Google Scholar 

  95. Burns FJ, Vanderlaan M, Sivak A, Albert RE (1976) Regression kinetics of mouse skin papillomas. Cancer Res 36:1422–1427

    CAS  PubMed  Google Scholar 

  96. Yuspa SH (1994) The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. Cancer Res 54:1178–1189

    CAS  PubMed  Google Scholar 

  97. Hennings H, Glick AB, Greenhalgh DA, Morgan DL, Strickland JE, Tennenbaum T, Yuspa SH (1993) Critical aspects of initiation, promotion, and progression in multistage epidermal carcinogenesis. Proc Soc Exp Biol Med 202:1–8

    Article  CAS  PubMed  Google Scholar 

  98. Rubin H (2007) Ordered heterogeneity and its decline in cancer and aging. Adv Cancer Res 98:117–147

    Article  CAS  PubMed  Google Scholar 

  99. Bissell MJ, Inman J (2008) Reprogramming stem cells is a microenvironmental task. Proc Natl Acad Sci U S A 105(41):15637–15638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Xu R, Boudreau A, Bissell MJ (2009) Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices. Cancer Metastasis Rev 28(1-2):167–176

    Article  PubMed  PubMed Central  Google Scholar 

  101. Gambichler T, Rotterdam S, Tigges C, Altmeyer P, Bechara FG (2008) Impact of ultraviolet radiation on the expression of marker proteins of gap and adhesion junctions in human epidermis. Photodermatol Photoimmunol Photomed 24(6):318–321

    Article  CAS  PubMed  Google Scholar 

  102. El-Abaseri TB, Putta S, Hansen LA (2006) Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis 27(2):225–231

    Article  CAS  PubMed  Google Scholar 

  103. Donahue SL, Lin Q, Cao S, Ruley HE (2006) Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability. Proc Natl Acad Sci U S A 103(31):11642–11646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zong C, Lu S, Chapman AR, Xie XS (2012) Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338(6114):1622–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bergstresser PR, Pariser RJ, Taylor JR (1978) Counting and sizing of epidermal cells in normal human skin. J Invest Dermatol 70:280–284

    Article  CAS  PubMed  Google Scholar 

  106. Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1(2):157–162

    Article  CAS  PubMed  Google Scholar 

  107. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH, Scott MP (1997) Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276:817–821

    Article  CAS  PubMed  Google Scholar 

  108. Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC, Dlugosz AA (2000) Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet 24(3):216–217

    Article  CAS  PubMed  Google Scholar 

  109. Stein WD (1991) Analysis of cancer incidence data on the basis of multistage and clonal growth models. Adv Cancer Res 56:161–213

    Article  CAS  PubMed  Google Scholar 

  110. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113

    Article  CAS  PubMed  Google Scholar 

  111. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordonez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A, Mudie LJ, Ning Z, Royce T, Schulz-Trieglaff OB, Spiridou A, Stebbings LA, Szajkowski L, Teague J, Williamson D, Chin L, Ross MT, Campbell PJ, Bentley DR, Futreal PA, Stratton MR (2009) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463(7278):191–196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordonez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF, Costa GL, Lee CC, Minna JD, Gazdar A, Birney E, Rhodes MD, McKernan KJ, Stratton MR, Futreal PA, Campbell PJ (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463(7278):184–190

    Article  CAS  PubMed  Google Scholar 

  114. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44(9):1006–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bozic I, Antal T, Ohtsuki H, Carter H, Kim D, Chen S, Karchin R, Kinzler KW, Vogelstein B, Nowak MA (2010) Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A 107:18545–18550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rubin H (2006) What keeps cells in tissues behaving normally in the face of myriad mutations? Bioessays 28(5):515–524

    Article  CAS  PubMed  Google Scholar 

  118. Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396(6709):336–342

    Article  CAS  PubMed  Google Scholar 

  119. Ruden DM, Garfinkel MD, Sollars VE, Lu X (2003) Waddington’s widget: Hsp90 and the inheritance of acquired characters. Semin Cell Dev Biol 14(5):301–310

    Article  CAS  PubMed  Google Scholar 

  120. Dai C, Whitesell L, Rogers AB, Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130(6):1005–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M (2011) Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469(7330):356–361

    Article  CAS  PubMed  Google Scholar 

  122. Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, Raine K, Jones D, Marshall J, Ramakrishna M, Shlien A, Cooke SL, Hinton J, Menzies A, Stebbings LA, Leroy C, Jia M, Rance R, Mudie LJ, Gamble SJ, Stephens PJ, McLaren S, Tarpey PS, Papaemmanuil E, Davies HR, Varela I, McBride DJ, Bignell GR, Leung K, Butler AP, Teague JW, Martin S, Jonsson G, Mariani O, Boyault S, Miron P, Fatima A, Langerod A, Aparicio SA, Tutt A, Sieuwerts AM, Borg A, Thomas G, Salomon AV, Richardson AL, Borresen-Dale AL, Futreal PA, Stratton MR, Campbell PJ (2012) The life history of 21 breast cancers. Cell 149(5):994–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Campbell PJ, Pleasance ED, Stephens PJ, Dicks E, Rance R, Goodhead I, Follows GA, Green AR, Futreal PA, Stratton MR (2008) Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci U S A 105(35):13081–13086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Novelli M, Cossu A, Oukrif D, Quaglia A, Lakhani S, Poulsom R, Sasieni P, Carta P, Contini M, Pasca A, Palmieri G, Bodmer W, Tanda F, Wright N (2003) X-inactivation patch size in human female tissue confounds the assessment of tumor clonality. Proc Natl Acad Sci U S A 100(6):3311–3314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Parsons BL (2008) Many different tumor types have polyclonal tumor origin: evidence and implications. Mutat Res 659(3):232–247

    Article  CAS  PubMed  Google Scholar 

  126. Merritt AJ, Gould KA, Dove WF (1997) Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant loss of Apc+ from all tumor lineages. Proc Natl Acad Sci U S A 94(25):13927–13931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Winton DJ, Blount MA, Ponder BA (1989) Polyclonal origin of mouse skin papillomas. Br J Cancer 60(1):59–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Pawelek JM, Chakraborty AK (2008) Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer 8(5):377–386

    Article  CAS  PubMed  Google Scholar 

  129. Ewald PW, Swain Ewald HA (2012) Infection, mutation, and cancer evolution. J Mol Med (Berl) 90(5):535–541

    Article  CAS  Google Scholar 

  130. Waddington CH (1942) Canalization of development and the inheritance of acquired characters. Nature 150:563–565

    Article  Google Scholar 

  131. Schmalhausen II (1986) Factors of evolution : the theory of stabilizing selection. University of Chicago Press, Chicago

    Google Scholar 

  132. Stoltzfus A (2006) Mutationism and the dual causation of evolutionary change. Evol Dev 8(3):304–317

    Article  PubMed  Google Scholar 

  133. Schoellnberger H, Beerenwinkel N, Hoogenveen R, Vineis P (2010) Cell selection as driving force in lung and colon carcinogenesis. Cancer Res 70:6797–6803

    Article  CAS  Google Scholar 

  134. Ruch RJ, Trosko JE (2001) Gap-junction communication in chemical carcinogenesis. Drug Metab Rev 33:117–124

    Article  CAS  PubMed  Google Scholar 

  135. Brash DE (1996) Cellular proofreading. Nat Med 2:525–526

    Article  CAS  PubMed  Google Scholar 

  136. Brash D, Cairns J (2009) The mysterious steps in carcinogenesis: addendum. Br J Cancer 101(8):1490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Benditt EP, Benditt JP (1973) Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci U S A 70:1753–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Andreassi MG, Botto N, Colombo MG, Biagini A, Clerico A (2000) Genetic instability and atherosclerosis: can somatic mutations account for the development of cardiovascular diseases? Environ Mol Mutagen 35(4):265–269

    Article  CAS  PubMed  Google Scholar 

  139. Levins R (1970) Complex systems. In: Waddington CH (ed) Towards a theoretical biology, vol 3. Aldine, Chicago, p 73

    Google Scholar 

  140. Levins R (1973) The limits of complexity. In: Pattee HA (ed) Hierarchy theory. George Braziller, New York, pp 111–127

    Google Scholar 

  141. Pienta KJ, McGregor N, Axelrod R, Axelrod DE (2008) Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. Transl Oncol 1(4):158–164

    Article  PubMed  PubMed Central  Google Scholar 

  142. Gatenby RA, Silva AS, Gillies RJ, Frieden BR (2009) Adaptive therapy. Cancer Res 69(11):4894–4903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

I thank John Cairns, Allon Klein, Dennis Chao, Phil Jones, Ben Simons, Bill Thilly, James Sherley, Harry Rubin, and the late Jan Pontén for many insightful conversations. Also Lena Gostjeva for the photograph in Fig. 5.1 and Alan Jonason, Annemarie Ziegler, Fredrik Pontén, Norbert Wikonkal, Eva Remenyik, Wengeng Zhang, Cathy Adrada, Meiling Zhu, and Doug Grossman for a collegial experimental environment.

Author information

Authors and Affiliations

  1. Department of Therapeutic Radiology, Yale School of Medicine, 333 Cedar St./ HRT 213, New Haven, CT, 06525-8040, USA

    Douglas E. Brash

Authors
  1. Douglas E. Brash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas E. Brash .

Editor information

Editors and Affiliations

  1. Biodesign Institute, School of Life Sciences, Arizona State University, Tempe, Arizona, USA

    Carlo C. Maley

  2. Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom

    Mel Greaves

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag New York

About this chapter

Cite this chapter

Brash, D.E. (2016). How Do Mutant Clones Expand in Normal Tissue?. In: Maley, C., Greaves, M. (eds) Frontiers in Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6460-4_5

Download citation

Publish with us

Policies and ethics

Search

Navigation