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Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics

Abstract

For at least 30 years cancer has been defined as a genetic disease and explained by the so-called somatic mutation theory (SMT), which has dominated the carcinogenesis field. Criticism of the SMT has recently greatly increased, although still not enough to force all SMT supporters to recognize its limits. Various researchers point out that cancer appears to be a complex process concerning a whole tissue; and that genomic mutations, although variably deleterious and unpredictably important in determining the establishment of the neoplastic phenotype, are not the primary origin for a malignant neoplasia. We attempt to describe the inadequacies of the SMT and demonstrate that epigenetics is a more logical cause of carcinogenesis. Many previous models of carcinogenesis fall into two classes: (i) in which some biological changes inside cells alone lead to malignancy; and (ii) requiring changes in stroma/extracellular matrix. We try to make clear that in the (ii) model genomic instability is induced by persistent signals coming from the microenvironment, provoking epigenetic and genetic modifications in tissue stem cells that can lead to cancer. In this perspective, stochastic mutations of DNA are a critical by-product rather then the primary cause of cancer. Indirect support for such model of carcinogenesis comes from the in vitro and vivo experiments showing apparent ‘reversion’ of cancer phenotypes obtained via physiological factors of cellular differentiation (cytokines and other signaling molecules) or drugs, even if the key mutations are not ‘reversed’.

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References

  1. Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799

    CAS  PubMed  Google Scholar 

  2. Holland AJ, Cleveland DW (2009) Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 10:478–487. doi:10.1038/nrm2

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Herrera LA, Prada D, Andonegui MA, Dueñas-González A (2008) The epigenetic origin of aneuploidy. Curr Genomics 9:43–50. doi:10.2174/138920208783884883

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Boveri T (1902) Über mehrpolige Mitosen als Mittel zur Analyse des Zellkerns. [Concerning multipolar mitoses as a means of analysing the cell nucleus.] C. Kabitzch, Würzburg and Verh. d. phys. med. Ges. zu Würzburg NF, Bd. 35

  5. Boveri T (2008) Concerning The Origin of Malignant Tumours. Journal of Cell Science 121:1–84. doi:10.1242/jcs.025742. http://www.newworldencyclopedia.org/entry/Cancer#cite_note-12

  6. Nordling CO (1953) A new theory on the cancer-inducing mechanism. Br J Cancer 7:68–72. doi:10.1038/bjc.1953.8

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Knudson A (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    PubMed Central  PubMed  Google Scholar 

  8. Feinberg AP, Vogelstein B, Droller MJ, Baylin SB, Nelkin BD (1983) Mutation affecting the 12th amino acid of the c-Ha-ras oncogene product occurs infrequently in human cancer. Science 220:1175–1177

    CAS  PubMed  Google Scholar 

  9. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    CAS  PubMed  Google Scholar 

  10. Klein G (1981) The role of gene dosage and genetic transpositions in carcinogenesis. Nature 294:313–318

    CAS  PubMed  Google Scholar 

  11. Rowley JD (1998) The critical role of chromosome translocations in human leukemias. Annu Rev Genet 32:495–519

    CAS  PubMed  Google Scholar 

  12. Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079

    CAS  PubMed  Google Scholar 

  13. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 7(100):57–70

    Google Scholar 

  14. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 4(144):646–674. doi:10.1016/j.cell.2011.02.013

    Google Scholar 

  15. Floor SL, Dumont JE, Maenhaut C, Raspe E (2012) Hallmarks of cancer: of all cancer cells, all the time? Trends Mol Med 18:509–515. doi:10.1016/j.molmed.2012.06.005

    CAS  PubMed  Google Scholar 

  16. Delys L, Detours V, Franc B, Thomas G, Bogdanova T, Tronko M, Libert F, Dumont JE, Maenhaut C (2007) Gene expression and the biological phenotype of papillary thyroid carcinomas. Oncogene 26:7894–7903

    CAS  PubMed  Google Scholar 

  17. Tomás G, Tarabichi M, Gacquer D, Hébrant A, Dom G, Dumont JE, Keutgen X, Fahey TJ, Maenhaut C, Detours V (2012) A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic. Oncogene 31:4490–4498. doi:10.1038/onc.2011.626

    PubMed  Google Scholar 

  18. Bertram JS (2000) The molecular biology of cancer. Mol Aspects Med 21:167–223

    CAS  PubMed  Google Scholar 

  19. Croce CM (2008) Oncogenes and cancer. N Engl J Med 358:502–511. doi:10.1056/NEJMra072367

    CAS  PubMed  Google Scholar 

  20. Kinzler KW, Vogelstein B (1997) Gatekeepers and caretakers. Nature 386(761):763

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Wodarz D (2005) Somatic evolution of cancer cells. Semin Cancer Biol 15:436–450

    Google Scholar 

  23. Vineis P (2003) Cancer as an evolutionary process at the cell level: an epidemiological perspective. Carcinogenesis 24:1–6

    CAS  PubMed  Google Scholar 

  24. Vineis P, Berwick M (2006) The population dynamics of cancer: a Darwinian perspective. Int J Epidemiol 35:1151–1159

    PubMed  Google Scholar 

  25. DePinho RA (2000) The age of cancer. Nature 408:248–254

    CAS  PubMed  Google Scholar 

  26. Balducci L, Ershler WB (2005) Cancer and ageing: a nexus at several levels. Nat Rev Cancer 5:655–662

    CAS  PubMed  Google Scholar 

  27. Gorbunova V, Seluanov A, Mao Z, Hine C (2007) Changes in DNA repair during aging. Nucleic Acids Res 35:7466–7474

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Das K, Wu R (2008) A statistical model for the identification of genes governing the incidence of cancer with age. Theor Biol Med Model 5:7. doi:10.1186/1742-4682-5-7

    PubMed Central  PubMed  Google Scholar 

  29. Soto AM, Sonnenschein C (2004) The somatic mutation theory of cancer: growing problems with the paradigm? BioEssays 26:1097–1107

    CAS  PubMed  Google Scholar 

  30. Van Regenmortel MH (2004) Biological complexity emerges from the ashes of genetic reductionism. J Mol Recognit 17:145–148

    PubMed  Google Scholar 

  31. Sonnenschein C, Soto AM (2000) Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog 29:205–211

    CAS  PubMed  Google Scholar 

  32. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379

    CAS  PubMed  Google Scholar 

  33. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    CAS  PubMed  Google Scholar 

  34. Mbeunkui F, Johann DJ Jr (2009) Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol 63:571–582. doi:10.1007/s00280-008-0881-9

    PubMed Central  PubMed  Google Scholar 

  35. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C (2004) The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 117(Pt 8):1495–1502

    CAS  PubMed  Google Scholar 

  36. Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849

    CAS  PubMed  Google Scholar 

  37. Radisky ES, Radisky DC (2007) Stromal induction of breast cancer: inflammation and invasion. Rev Endocr Metab Disord 8:279–287

    PubMed  Google Scholar 

  38. Hu M, Yao J, Cai L, Bachman KE, van den Brûle F, Velculescu V, Polyak K (2005) Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 37:899–905

    CAS  PubMed  Google Scholar 

  39. Fiegl H, Millinger S, Goebel G, Müller-Holzner E, Marth C, Laird PW, Widschwendter M (2006) Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res 66:29–33

    CAS  PubMed  Google Scholar 

  40. Streubel B, Chott A, Huber D, Exner M, Jäger U, Wagner O, Schwarzinger I (2004) Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 351:250–259

    CAS  PubMed  Google Scholar 

  41. Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, Shun CT, Tsai MF, Chen CH, Yang PC (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23:953–964

    CAS  PubMed  Google Scholar 

  42. Elenbaas B, Weinberg RA (2001) Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 264:169–184

    CAS  PubMed  Google Scholar 

  43. Sternlicht MD, Kedeshian P, Shao ZM, Safarians S, Barsky SH (1997) The human myoepithelial cell is a natural tumor suppressor. Clin Cancer Res 3:1949–1958

    CAS  PubMed  Google Scholar 

  44. Soto AM, Sonnenschein C (2005) Emergentism as a default: cancer as a problem of tissue organization. J Biosci 30:103–118

    CAS  PubMed  Google Scholar 

  45. Markey CM, Luque EH, Munoz De Toro M, Sonnenschein C, Soto AM (2001) In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod 65:1215–1223

    CAS  PubMed  Google Scholar 

  46. Soto AM, Vandenberg LN, Maffini MV, Sonnenschein C (2008) Does breast cancer start in the womb? Basic Clin Pharmacol Toxicol 102:125–133

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Soto AM, Maffini MV, Sonnenschein C (2008) Neoplasia as development gone awry: the role of endocrine disruptors. Int J Androl 31:288–293

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Heng HH (2007) Cancer genome sequencing: the challenges ahead. BioEssays 29:783–794

    PubMed  Google Scholar 

  49. Heng HH (2008) The gene-centric concept: a new liability? BioEssays 30:196–197. doi:10.1002/bies.20711

    PubMed  Google Scholar 

  50. Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33

    CAS  PubMed  Google Scholar 

  51. Duesberg P, Rasnick D (2000) Aneuploidy, the somatic mutation that makes cancer a species of its own. Cell Motil Cytoskeleton 47:81–107

    CAS  PubMed  Google Scholar 

  52. Duesberg P, Li R, Rasnick D, Rausch C, Willer A, Kraemer A, Yerganian G, Hehlmann R (2000) Aneuploidy precedes and segregates with chemical carcinogenesis. Cancer Genet Cytogenet 119:83–93

    CAS  PubMed  Google Scholar 

  53. Duesberg P, Li R, Fabarius A, Hehlmann R (2005) The chromosomal basis of cancer. Cell Oncol 27:293–318

    CAS  PubMed  Google Scholar 

  54. Duesberg P, Li R, Fabarius A, Hehlmann R (2006) Aneuploidy and cancer: from correlation to causation. Contrib Microbiol 13:16–44

    PubMed  Google Scholar 

  55. Satgé D, Bénard J (2008) Carcinogenesis in Down syndrome: what can be learned from trisomy 21? Semin Cancer Biol 18:365–371. doi:10.1016/j.semcancer.2008.03.020

    PubMed  Google Scholar 

  56. 1999–2007 Cancer Incidence and Mortality Data (2007) National Program of Cancer Registries. Betesda, Mary- land, USA CDC

  57. Dix D (2003) On the role of genes relative to the environment in carcinogenesis. Mech Ageing Dev 124:323–332

    PubMed  Google Scholar 

  58. Nachman KE, Fox M, Sheehan MC, Burke TA, Rodricks JV, Woodruff TJ (2011) Leveraging epidemiology to improve risk assessment. Open Epidemiolgy J 4:3–29

    Google Scholar 

  59. Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920

    PubMed  Google Scholar 

  60. Hoover RN (2000) Cancer–nature, nurture, or both. N Engl J Med 343:135–136

    CAS  PubMed  Google Scholar 

  61. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85

    CAS  PubMed  Google Scholar 

  62. Briggs D (2003) Environmental pollution and the global burden of disease. Br Med Bull 68:1–24

    CAS  PubMed  Google Scholar 

  63. Cohen AJ, Ross Anderson H, Ostro B, Pandey KD, Krzyzanowski M, Künzli N, Gutschmidt K, Pope A, Romieu I, Samet JM, Smith K (2005) The global burden of disease due to outdoor air pollution. J Toxicol Environ Health A 68:1301–1307

    CAS  PubMed  Google Scholar 

  64. Vineis P, Xun W (2009) The emerging epidemic of environmental cancers in developing countries. Ann Oncol 20:205–212. doi:10.1093/annonc/mdn596

    CAS  PubMed  Google Scholar 

  65. Bleyer A, O’Leary M, Barr R, Ries LA (eds) (2006) Cancer epidemiology in older adolescents and young adults 15–29 years of age, including SEER incidence and survival: 1975–2000. NIH Pub. No. 06-5767. National Cancer Institute, Bethesda (MD)

    Google Scholar 

  66. Pritchard-Jones K, Kaatsch P, Steliarova-Foucher E, Stiller C, Coebergh JW (2006) Cancer in children and adolescents in Europe. Eur J Cancer 42:2183–2190

    CAS  PubMed  Google Scholar 

  67. Greaves MF, Maia AT, Wiemels JL, Ford AM (2003) Leukemia in twins: lessons in natural history. Blood 102:2321–2333

    CAS  PubMed  Google Scholar 

  68. Greaves M (2003) Pre-natal origins of childhood leukaemia. Rev Clin Exp Hematol 7:233–245

    CAS  PubMed  Google Scholar 

  69. Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, Hows JM, Navarrete C, Greaves M (2002) Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA 99:8242–8247

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Greaves M (2005) In utero origins of childhood leukaemia. Early Hum Dev 81:123–129

    PubMed  Google Scholar 

  71. Esteller M (2007) Cancer epigenomics: dNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298

    CAS  PubMed  Google Scholar 

  72. Gerstein MB, Bruce C, Rozowsky JS, Zheng D, Du J, Korbel JO, Emanuelsson O, Zhang ZD, Weissman S, Snyder M (2007) What is a gene, post-ENCODE? History and updated definition. Genome Res 17(6):669–681

    CAS  Google Scholar 

  73. Mazzocchi F (2008) Complexity in biology. Exceeding the limits of reductionism and determinism using complexity theory. EMBO Rep 9(1):10–14. doi:10.1038/sj.embor.7401147

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Shapiro JA (2013) How life changes itself: the Read-Write (RW) genome. Phys Life Rev 10(3):287–323. doi:10.1016/j.plrev.2013.07.001

    PubMed  Google Scholar 

  75. Radisky D, Hagios C, Bissell MJ (2001) Tumors are unique organs defined by abnormal signaling and context. Semin Cancer Biol 11(2):87–95

    CAS  PubMed  Google Scholar 

  76. Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46–54

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Redig AJ, McAllister SS (2013) Breast cancer as a systemic disease: a view of metastasis. J Intern Med 274(2):113–126. doi:10.1111/joim.12084

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Bizzarri M, Cucina A, Conti F (2008) D’Anselmi F Beyond the oncogene paradigm: understanding complexity in cancerogenesis. Acta Biotheor 56(3):173–196. doi:10.1007/s10441-008-9047-8

    CAS  PubMed  Google Scholar 

  79. Levin M (2012) Morphogenetic fields in embryogenesis, regeneration, and cancer: non-local control of complex patterning, Biosystems 109(3):243–621. doi: 10.1016/j.biosystems.2012.04.005

  80. Baccarelli A, Hirt C, Pesatori AC, Consonni D, Patterson DG Jr, Bertazzi PA, Dölken G, Landi MT (2006) t(14;18) translocations in lymphocytes of healthy dioxin-exposed individuals from Seveso, Italy. Carcinogenesis 27:2001–2007

    CAS  PubMed  Google Scholar 

  81. Agopian J, Navarro JM, Gac AC, Lecluse Y, Briand M, Grenot P, Gauduchon P, Ruminy P, Lebailly P, Nadel B, Roulland S (2009) Agricultural pesticide exposure and the molecular connection to lymphomagenesis. J Exp Med 206:1473–1483. doi:10.1084/jem.20082842

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Hayday AC, Gillies SD, Saito H, Wood C, Wiman K, Hayward WS, Tonegawa S (1984) Activation of a translocated human c-myc gene by an enhancer in the immunoglobulin heavy-chain locus. Nature 307:334–340

    CAS  PubMed  Google Scholar 

  83. Kurtulus S, Tripathi P, Moreno-Fernandez ME, Sholl A, Katz JD, Grimes HL, Hildeman DA (2011) Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim. J Immunol 186:5729–5737. doi:10.4049/jimmunol.1100102

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Finke J, Fritzen R, Ternes P, Trivedi P, Bross KJ, Lange W, Mertelsmann R, Dölken G (1992) Expression of bcl-2 in Burkitt’s lymphoma cell lines: induction by latent Epstein–Barr virus genes. Blood 80:459–469

    CAS  PubMed  Google Scholar 

  85. Strohman RC (1997) The coming Kuhnian revolution in biology. Nat Biotechnol 15:194–200

    CAS  PubMed  Google Scholar 

  86. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45

    CAS  PubMed  Google Scholar 

  87. Turner BM (2002) Cellular memory and the histone code. Cell 111:285–291

    CAS  PubMed  Google Scholar 

  88. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167

    CAS  PubMed  Google Scholar 

  89. Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174

    CAS  PubMed  Google Scholar 

  90. Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB, Herman JG (1999) hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol 155:1767–1772

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Schuebel KE, Chen W, Cope L, Glockner SC, Suzuki H, Yi JM, Chan TA, Van Neste L, Van Criekinge W, van den Bosch S, van Engeland M, Ting AH, Jair K, Yu W, Toyota M, Imai K, Ahuja N, Herman JG, Baylin SB (2007) Comparing the DNA hypermethylome with gene mutations in human colorectal cancer. PLoS Genet 3:1709–1723

    CAS  PubMed  Google Scholar 

  92. Chen SS, Raval A, Johnson AJ, Hertlein E, Liu TH, Jin VX, Sherman MH, Liu SJ, Dawson DW, Williams KE, Lanasa M, Liyanarachchi S, Lin TS, Marcucci G, Pekarsky Y, Davuluri R, Croce CM, Guttridge DC, Teitell MA, Byrd JC, Plass C (2009) Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proc Natl Acad Sci USA 106:13433–13438

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Karpinets TV, Foy BD (2005) Tumorigenesis: the adaptation of mammalian cells to sustained stress environment by epigenetic alterations and succeeding matched mutations. Carcinogenesis 26:1323–1334

    CAS  PubMed  Google Scholar 

  94. Cheung HH, Lee TL, Rennert OM, Chan WY (2009) DNA methylation of cancer genome. Birth Defects Res C Embryo Today 87:335–350. doi:10.1002/bdrc.20163

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Rollins RA, Haghighi F, Edwards JR, Das R, Zhang MQ, Ju J, Bestor TH (2006) Large-scale structure of genomic methylation patterns. Genome Res 16:157–163

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R, Herb B, Ladd-Acosta C, Rho J, Loewer S, Miller J, Schlaeger T, Daley GQ, Feinberg AP (2009) Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41:1350–1353. doi: 10.1038/ng.471

  97. Jelinic P, Shaw P (2007) Loss of imprinting and cancer. J Pathol 211:261–268

    CAS  PubMed  Google Scholar 

  98. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92

    CAS  PubMed  Google Scholar 

  99. Cheah MS, Wallace CD, Hoffman RM (1984) Hypomethylation of DNA in human cancer cells: a site-specific change in the c-myc oncogene. J Natl Cancer Inst 73:1057–1065

    CAS  PubMed  Google Scholar 

  100. Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56. doi:10.1016/B978-0-12-380866-0.60002-2

    PubMed  Google Scholar 

  101. Luczak MW, Jagodziński PP (2006) The role of DNA methylation in cancer development. Folia Histochem Cytobiol 44:143–154

    CAS  PubMed  Google Scholar 

  102. Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP (1991) Allele specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 48:880–888

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM et al (1994) Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91:9700–9704

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D (1995) 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1:686–692

    CAS  PubMed  Google Scholar 

  105. Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB (1995) Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55:4525–4530

    CAS  PubMed  Google Scholar 

  106. Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054

    CAS  PubMed  Google Scholar 

  107. Geutjes EJ, Bajpe PK, Bernards R (2012) Targeting the epigenome for treatment of cancer. Oncogene 31:3827–3844. doi:10.1038/onc.2011.552

    CAS  PubMed  Google Scholar 

  108. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

    CAS  PubMed  Google Scholar 

  109. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ (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

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Shapiro JA (2009) Revisiting the central dogma in the 21st century. Ann N Y Acad Sci 1178:6–28. doi:10.1111/j.1749-6632.2009.04990.x

    CAS  PubMed  Google Scholar 

  111. Hauptmann S, Schmitt WD (2006) Transposable elements—is there a link between evolution and cancer? Med Hypotheses 66:580–591

    CAS  PubMed  Google Scholar 

  112. Soto AM, Maffini MV, Sonnenschein C (2008) Neoplasia as development gone awry: the role of endocrine disruptors. Int J Androl 31:288–293

    PubMed Central  CAS  PubMed  Google Scholar 

  113. López-Maury L, Marguerat S, Bähler J (2008) Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat Rev Genet 9:583–593. doi:10.1038/nrg2398

    PubMed  Google Scholar 

  114. Cyr AR, Domann FE (2011) The redox basis of epigenetic modifications: from mechanisms to functional consequences. Antioxid Redox Signal 15:551–589. doi:10.1089/ars.2010.3492

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Vineis P, Schatzkin A, Potter JD (2010) Models of carcinogenesis: an overview. Carcinogenesis 31(10):1703–1709. doi:10.1093/carcin/bgq087

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Remak R (1854) Ein beitrag zur entwickelungsgeschichte der krebshaften geschwulste. Deut Klin 6:70–174

    Google Scholar 

  117. Conheim J (1875) Congenitales, quergestreiftes muskelsarkon der nireren. Virchows Arch 65:64

    Google Scholar 

  118. Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51:1–28

    PubMed  Google Scholar 

  119. Durante F (1874) Nesso fisio-pathologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni. Arch Memori ed Osservazioni di Chirugia Practica 11:217–226

    Google Scholar 

  120. Cohnhein J (1889) Lectures in general pathology. The New Sydenham Society, London

    Google Scholar 

  121. Rippert V (1904) Ueber ein myosarcoma striocellulare des nierenbeckens und des ureters. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin 106:282–295

    Google Scholar 

  122. Rippert V (1911) Das carcinom des menschen. F. Cohen, Bonn

    Google Scholar 

  123. Sander K (1994) Of gradients and genes: developmental concepts of Theodor Boveri and his students. Roux Arch Dev Biol 203:295–297

    Google Scholar 

  124. Gilbert SF, Opitz JM, Raff RA (1996) Resynthesizing evolutionary and developmental biology. Dev Biol 173:357–372

    CAS  PubMed  Google Scholar 

  125. Slaughter DP, Southwick HW, Smejkal W (1953) Field “cancerization” in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6:963–968

    CAS  PubMed  Google Scholar 

  126. Sell S (2010) On the stem cell origin of cancer. Am J Pathol 176:2584–2594. doi:10.2353/ajpath.2010.091064

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH (2003) A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63:1727–1730

    CAS  PubMed  Google Scholar 

  128. Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS (2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 33:1526–1530

    CAS  PubMed  Google Scholar 

  129. Askanazy M (1907) Die Teratome nach ihrem Bau, ihrem Verlauf, ihrer Genese und im Vergleich zum experimentellen Teratoid. Verhandl Deutsch Pathol 11:39–82

    Google Scholar 

  130. Martin CR (1980) Teratocarcinomas and mammalian embriogenesis. Science 209:768–776

    CAS  PubMed  Google Scholar 

  131. Illmensee K, Mintz B (1976) Totipotency and normal differentiation of single teratocarcinoma cell cloned by injection into blastocysts. Proc Natl Acad Sci USA 73:549–553

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Mintz B, Ilmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72:3585–3589

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Papaioannou VE, Gardner RL, Mc Burney MV, Babinet C, Evans MJ (1978) Participation of cultured teratocarcinoma cells in mouse embriogenesis. J Embriol Exp Morphol 44:93–104

    CAS  Google Scholar 

  134. Sachs L (1995) The adventures of a biologist: prenatal diagnosis, hematopoiesis, leukemia, carcinogenesis and tumor suppression. Adv Cancer Res 66:1–40

    CAS  PubMed  Google Scholar 

  135. Telerman A, Amson R (2009) The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 9:206–216. doi:10.1038/nrc2589

    CAS  PubMed  Google Scholar 

  136. Ginsburg H, Sachs L (1963) Formation of pure suspensions of mast cells in tissue culture by differentiation of lymphoid cells from the mouse thymus. J Natl Cancer Inst 31:1–39

    CAS  PubMed  Google Scholar 

  137. Pluznik DH, Sachs L (1965) The cloning of normal mastcells in tissue culture. J Cell Comp Physiol 66:319–324

    CAS  Google Scholar 

  138. Ichikawa Y, Pluznik DH, Sachs L (1966) In vitro control of the development of macrophage and granulocyte colonies. Proc Natl Acad Sci USA 56:488–495

    PubMed Central  CAS  PubMed  Google Scholar 

  139. Pluznik DH, Sachs L (1966) The induction of clones of normal mast cells by a substance from conditioned medium. Exp Cell Res 43:553–563

    CAS  PubMed  Google Scholar 

  140. Sachs L (1987) The molecular control of blood cell development. Science 238:1374–1379

    CAS  PubMed  Google Scholar 

  141. Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530

    CAS  PubMed  Google Scholar 

  143. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6:1229–1234

    CAS  PubMed  Google Scholar 

  144. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377

    CAS  PubMed  Google Scholar 

  145. Sell S (2006) Stem cells in hepatocarcinogenesis. Cell Sci Rev 3:1742–8130

    Google Scholar 

  146. Pierce GB (1983) The cancer cell and its control by the embryo. Am J Pathol 113:117–124

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Potter VR (1978) Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. Br J Cancer 38:1–23

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902

    CAS  PubMed  Google Scholar 

  149. Lotem J, Sachs L (2002) Epigenetics wins over genetics: induction of differentiation in tumor cells. Semin Cancer Biol 12:339–346

    CAS  PubMed  Google Scholar 

  150. Cruz FD, Matushansky I (2012) Solid tumor differentiation therapy—is it possible? Oncotarget 3:559–567

    PubMed  Google Scholar 

  151. Pierce GB Jr, Verney EL (1961) An in vitro and in vivo study of differentiation in teratocarcinomas. Cancer 14:1017–1029

    PubMed  Google Scholar 

  152. Nowak D, Stewart D, Koeffler HP (2009) Differentiation therapy of leukemia: 3 decades of development. Blood 113:3655–3665

    PubMed Central  CAS  PubMed  Google Scholar 

  153. Huang ME1, Ye YC, Chen SR, Chai JR, Lu JX, Zhao L, Gu LJ, Wang ZY (1989) Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Haematol Blood Transfus 32: 88–96

  154. Xu WP1, Zhang X, Xie WF (2014) Differentiation therapy for solid tumors J Dig Dis 15(4):159–165. doi: 10.1111/1751-2980.12122

  155. Sachs L (1990) The control of growth and differentiation in normal and leukemic blood cells. Cancer 65:2196–2206

    CAS  PubMed  Google Scholar 

  156. Lotem J, Sachs L (2002) Cytokine control of developmental programs in normal hematopoiesis and leukemia. Oncogene 21:3284–3294

    CAS  PubMed  Google Scholar 

  157. Fibach E, Landau T, Sachs L (1972) Normal differentiation of myeloid leukaemic cells induced by a differentiation-inducing protein. Nat New Biol 237:276–278

    CAS  PubMed  Google Scholar 

  158. Olsson I, Arnljots K, Gullberq U, Lantz M, Peetre C, Richter J (1988) Myeloid cell differentiation: the differentiation inducing factors of myeloid leukemia cells. Leukemia 2:16S–23S

    CAS  PubMed  Google Scholar 

  159. Spira AI, Carducci MA (2003) Differentiation therapy. Curr Opin Pharmacol 3:338–343

    CAS  PubMed  Google Scholar 

  160. Fibach E, Hayashi M, Sachs L (1973) Control of normal differentiation of myeloid leukemic cells to macrophages and granulocytes. Proc Natl Acad Sci USA 70:343–346

    PubMed Central  CAS  PubMed  Google Scholar 

  161. Lotem J, Sachs L (1974) Different blocks in the differentiation of myeloid leukemic cells. Proc Natl Acad Sci USA 71:3507–3511

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Sachs L (1982) Normal developmental programmes in myeloid leukemia: regulatory proteins in the control of growth and differentiation. Cancer Surv 1:321–342

    Google Scholar 

  163. Cohen L, Sachs L (1981) Constitutive gene expression in myeloid leukemia and cell competence for induction of differentiation by the steroid dexamethasone. Proc Natl Acad Sci USA 78:353–357

    PubMed Central  CAS  PubMed  Google Scholar 

  164. Gootwine E, Webb CG, Sachs L (1982) Participation of myeloid leukaemic cells injected into embryos in haematopoietic differentiation in adult mice. Nature 299:63–65

    CAS  PubMed  Google Scholar 

  165. Webb CG, Gootwine E, Sachs L (1984) Developmental potential of myeloid leukemia cells injected into midgestation embryos. Dev Biol 101:221–224

    CAS  PubMed  Google Scholar 

  166. Sachs L (1996) The control of hematopoiesis and leukemia: from basic biology to the clinic. Proc Natl Acad Sci USA 93:4742–4749

    PubMed Central  CAS  PubMed  Google Scholar 

  167. Sachs L (1987) The Wellcome Foundation lecture, 1986. The molecular regulators of normal and leukaemic blood cells. Proc R Soc London B Biol Sci 231:289–312

    CAS  Google Scholar 

  168. Sachs L (1987) Cell differentiation and bypassing of genetic defects in the suppression of malignancy. Cancer Res 47:1981–1986

    CAS  PubMed  Google Scholar 

  169. Sachs L (1978) Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature 274:535–539

    CAS  PubMed  Google Scholar 

  170. Marks PA, Rifkind RA (1978) Erythroleukemic differentiation. Annu Rev Biochem 47:419–448

    CAS  PubMed  Google Scholar 

  171. Degos L, Wang ZY (2001) All trans-retinoic acid in acute promyelocytic leukemia. Oncogene 20:7140–7145

    CAS  PubMed  Google Scholar 

  172. Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM, Wang X, Gallo M, Garzia L, Zayne K (2014) Epigenomic alterations define lethal CIMP-positive ependymonas of infancy. Nature 506:445–451. doi:10.1038/nature13108

    PubMed Central  CAS  PubMed  Google Scholar 

  173. Shapiro JA (2014) Epigenetic control of mobile DNA as an interface between experience and genome change. Front Genet 25(5):87. doi:10.3389/fgene.2014.00087

    Google Scholar 

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Burgio, E., Migliore, L. Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics. Mol Biol Rep 42, 777–790 (2015). https://doi.org/10.1007/s11033-014-3804-3

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Keywords

  • Carcinogenesis
  • Genetics
  • Epigenetics