SpringerLink
Log in

Cancer Is a Problem of Developmental Biology: Maturation Arrest and the Hierarchical Model of the Origin of Cancer from Stem Cells

  • Chapter
  • First Online:
Stem Cells Handbook

Abstract

The hierarchical model of the origin of cancer from stem cells posits that cancer cells arise from undifferentiated (in the case of germinal tumors) or tissue-determined stem cells during the process of tissue renewal due to a block in the ability of the cells of the lineage to differentiate. The state of differentiation of the cancer depends on the level of maturation at which the arrest occurs. If arrest occurs early in the maturation process the tumors will be poorly differentiated; if later, they will be more differentiated. Examples presented in this review are included for each of the major mechanisms by which cancers arise: field theory (teratocarcinoma); chemical exposure (hepatocellular carcinoma, epithelial (skin) cancer); mutations (leukemia, colon cancer); and epigenetic change (gastric cancer). In each of these examples there is a block in maturation whereby the tissue stem cell produces cancerous progeny that express a phenotype that allows for continued proliferation and inhibition of differentiation. Differentiation therapy is based on the concept of removing the block to maturation arrest.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Pierce GB, Shikes R, Fink LM. Cancer: a problem of developmental biology. Englewood Cliffs, NJ: Prentice Hall; 1978. p. 1–242.

    Google Scholar 

  2. Pierce GB, Spears WC. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res. 1988;48:1196–204.

    Google Scholar 

  3. Pierce BB, Wallace C. Differentiation of malignant to benign cells. Cancer Res. 1971;31:127–34.

    PubMed  CAS  Google Scholar 

  4. Sell S, Pierce GB. Biology of disease: maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest. 1994;70:6–21.

    PubMed  CAS  Google Scholar 

  5. Shimkin M. Contrary to nature. Washington, DC: NIH, USDOH; 1977.

    Google Scholar 

  6. Bainbridge WS. The cancer problem. New York: Macmillan; 1914.

    Google Scholar 

  7. Recamier JCA. Recherches sur the traitement du cancer: par la compression methodique simple ou combinee, et sur l’histoire General de la meme maladie, vol. 2. Paris: Gabon; 1829.

    Google Scholar 

  8. Remak R. Ein beitrag zur entwickelungsgeschichte der krebshaften geschwulste. Deut Klin. 1854;6:70–174.

    Google Scholar 

  9. Durante F. Nesso fisio-pathologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni. Arch Memor Osser Chir Pract. 1874;11:217–26.

    Google Scholar 

  10. Cohnheim J. Congenitales, quergestreiftes muskelsarkon der nireren. Virchows Arch. 1875;65:64.

    Article  Google Scholar 

  11. Osler W, McCrea T. Modern medicine: it’s theory and practice. Philadelphia: Lean and Febiger; 1913. p. 5254.

    Google Scholar 

  12. Virchow R. Dir krankhoften geschwulste, vol. II (pt. 1). Berlin: Onkologie; 1863.

    Google Scholar 

  13. Dixon FJ, Moore RA. Testicular tumors: a clinicopathological study. Cancer. 1953;6:417–43.

    Article  Google Scholar 

  14. Damjanov I. Pathobiology of human germ cell tumors. Recent Results Cancer Res. 1991;123:1–34.

    Article  PubMed  CAS  Google Scholar 

  15. Solter D, Damjanov I. Teratocarcinoma and the expression of oncodevelopmental genes. Methods Cancer Res. 1979;18: 277–98.

    Google Scholar 

  16. Chan D, Sell S. Tumor markers, chapter 23. In: Burtis CA, Ashwood ER, editors. Tietz textbook of clinical chemistry. 3rd ed. Philadelphia, PA: Saunders; 1999. p. 722–49.

    Google Scholar 

  17. Peyron A. Sur la presence des cellules genitales primordiales dans les boutons embryononnaires des embryomes parthenogenetiques chez l’homme. C R Acad Sci. 1938;206:1680–3.

    Google Scholar 

  18. Stevens LC. Experimental production of testicular teratomas in mice. Proc Natl Acad Sci USA. 1964;52:654–61.

    Article  PubMed  CAS  Google Scholar 

  19. Stevens LC. Origin of testicular teratomas from primordial germ cells in mice. J Natl Cancer Inst. 1967;38:549–52.

    PubMed  CAS  Google Scholar 

  20. Brinster RL. The effect of cells transferred into the mouse blastocyst on subsequent development. J Exp Med. 1974;140:1049–56.

    Article  PubMed  CAS  Google Scholar 

  21. Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA. 1975;72:3583–9.

    Google Scholar 

  22. Ilmmenesee K. Reversion of malignancy and normalized differentiation of teratocarcinoma cells in mammals. In: Russel LC, editor. Generic mosaics and chimeras in mammals. New York: Plenum; 1978. p. 3–25.

    Chapter  Google Scholar 

  23. Papaionnou VE, McBurney MW, Gardner RL, Evans RL. Fate of teratocarcinoma cells injected into early mouse embryos. Nature. 1975;258:70–3.

    Article  Google Scholar 

  24. Papaioannou VE. Ontogen, pathology, oncology. Int J Dev Biol. 1993;37:33–7.

    PubMed  CAS  Google Scholar 

  25. Pierce GB, Dixon FJ. The demonstration of teratogenesis by metamorphosis of multipotential cells. Cancer. 1959;12:573–83.

    Article  PubMed  CAS  Google Scholar 

  26. Pierce GM, Dixon FJ, Verney E. Teratocarcinogenic and tissue forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest. 1960;9:583–602.

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  28. Sun SY, Lotan R. Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol. 2002;41:41–55.

    Article  PubMed  Google Scholar 

  29. Sell S. On the stem cell origin of cancer. Am J Pathol. 2010;176:2584–94.

    Article  PubMed  CAS  Google Scholar 

  30. Einhorm L. Are there factors preventing cancer development during embryonic life? Oncodev Biol Med. 1982;4:219–29.

    Google Scholar 

  31. Rl B. Radiation teratogenesis. Teratology. 1980;21:281–98.

    Article  Google Scholar 

  32. Pierce GB. The cancer cell and its control by the embryo. Am J Pathol. 1983;113:116–24.

    Google Scholar 

  33. Pierce GB, Lewis SH, Miller GJ, Morits E, Miller P. Tumorigenicity of embryonal carcinoma as an assay to study control of malignancy by the murine blastocyst. Proc Natl Acad Sci USA. 1979;76:6649–51.

    Article  PubMed  CAS  Google Scholar 

  34. Pierce GB, Podesta A, Wells RS. The role of the blastocyst trophoderm in control of colony formation. In: Silver S, Strickland S, Martin G, editors. Teratocarcinoma stem cells, Cold Spring Harbor Symposium. New York; 1983. p. 15–22.

    Google Scholar 

  35. Pierce GB, Pantazis CG, Caldwell JE, Wells RS. Specificity of the control of tumor formation by blastocysts. Cancer Res. 1982;42(3):1082–7.

    PubMed  CAS  Google Scholar 

  36. Gershenson M, Graves K, Carson D, Wells RS, Pierce GB. Regulation of melanoma by the embryonic skin. Proc Natl Acad Sci USA. 1986;83:7307–10.

    Article  Google Scholar 

  37. Webb CW, Gootwine E, Sachs L. Developmental potential of myeloid leukemia cells injected into rat midgestation embryos. Dev Biol. 1984;101:221–4.

    Article  PubMed  CAS  Google Scholar 

  38. Coleman WB, Wennerberg AE, Smith GJ, Grisham JW. Regulation of differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment. Am J Pathol. 1993;142:1373–82.

    PubMed  CAS  Google Scholar 

  39. Weaver V, Petersen O, Wang F, Larabell C, Briand P, Damsky C, Bissel M. Reversion of the malignant phenotype of human breast cancer in three-dimensional culture and in vivo by integrin blocking bodies. J Cell Biol. 1997;137:231–45.

    Article  PubMed  CAS  Google Scholar 

  40. Postovit LM, Maragaryan NV, Seftor EA, et al. Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells. Proc Natl Acad Sci USA. 2008;18:105–11.

    Google Scholar 

  41. Hendrix MJ, Seftor EA, Seftor REB, Kaisermeier-Kulesa J, Duleas PM, Postovit LM. Reprogramming metastatic tumor cells with the embryonic microenvironment. Nat Rev Cancer. 2007;7:246–55.

    Article  PubMed  CAS  Google Scholar 

  42. Kulesa PM, Kasemeier-Kulesa JC, Teddy JM, Margaryan NV, Seftor EA, Seftor RE, Hendrix MJ. Reprogramming metastatic tumor cells to assume a neural crest-like phenotype in an embryonic microenvironment. Proc Natl Acad Sci USA. 2006;103:3752–7.

    Article  PubMed  CAS  Google Scholar 

  43. Gootwine E, Webb CG, Sachs L. Participation of myeloid leukemia cells injected into embryos in haematopoietic differentiation in adult mice. Nature. 1982;299:63–5.

    Article  PubMed  CAS  Google Scholar 

  44. Biava PM, Fiorito A, Negro C, Mariani M. Effect of treatment with embryonic and uterine tissue homogenates on Lewis lung carcinoma development. Cancer Lett. 1988;41:265–70.

    Article  PubMed  CAS  Google Scholar 

  45. Biava PM, Bonsignorio D, Hoxa M. Life-protecting factor (LPF): an anti-cancer low molecular weight fraction isolated from pregnant uterine mucosa during embryo organogenesis. J Tumor Marker Oncol. 2000;15:223–33.

    Google Scholar 

  46. Biava PM, Bonsignorio D, Hoxa M, Impagliazzo M, Frosi A, Larese F, Negro C. Mother-embryo cross-talk: the anti-cancer substances produced by mother and embryo during cell differentiation. A review of experimental data. J Tumor Marker Oncol. 2002;17:55–8.

    Google Scholar 

  47. McKinnel RG, Deggins BA, Labat DD. Transplantation of pluripotential nuclei from triploid from tumors. Science. 1996;165:294–396.

    Google Scholar 

  48. Li L, Connelly MC, Wetmore C, Currant T, Morgan JI. Mouse embryos cloned from brain tumors. Cancer Res. 2003;63:2733–7.

    PubMed  CAS  Google Scholar 

  49. Biava PM, Carluccio A. Activation of anti-oncogene p53 produced by embryonic extracts in vitro tumor cells. J Tumor Marker Oncol. 1977;12:9–15.

    Google Scholar 

  50. Biava PM, Bonsignorio D, Hoxa M, Facco R, Ielapi T, Frati L, Bizzarri M. Post-translational modification of the retinoblastoma protein (pRb) induced by in vitro administration of Zebrafish embryonic extracts on kidney adenocarcinoma cell line. J Tumor Marker Oncol. 2002;17:59–64.

    Google Scholar 

  51. Cucina A, Biava PM, D’Anselmi F, Coluccia P, Conti F, Di Clemente R, Miccheli A, Frati L, Gulino A, Bizzarri M. Zebrafish embryo proteins induce apoptosis in human colon cancer cells (Caco2). Apoptosis. 2006;9:1617–28.

    Article  Google Scholar 

  52. Biava PM, Basevi M, Biggiero L, Borgonovo A, Borgonovo E, Burigana F. Cancer cell reprogramming: stem cell differentiation stage factors and an agent based model to optimize cancer treatment. Curr Pharm Biotechnol. 2011;12:231–42.

    Article  PubMed  CAS  Google Scholar 

  53. Dobson, J. ‘Percivall Pott’ in Annals of The Royal College of Surgeons of England; 1972. vol. 50, p. 54–65.

    Google Scholar 

  54. Rehn L. Blasengeschwulse bei fuchsin-arbeitern. Arch Klin Chir. 1895;50:588–600.

    Google Scholar 

  55. Farber E. Similarities in the sequence of early histologic changes induced in the liver by ethionine, 2-acetylaminofluorene, and 3′-methyl−4-dimethylamionazobenzene. Cancer Res. 1956;16:142–8.

    PubMed  CAS  Google Scholar 

  56. Farber E. The multistep nature of cancer development. Cancer Res. 1984;44:4217–23.

    PubMed  CAS  Google Scholar 

  57. Abelev GI. Alphafetoprotein: the genesis. Oncodev Biol Med. 1983;4:371–81.

    PubMed  CAS  Google Scholar 

  58. Sell S. Alpha-fetoprotein, stem cells, and cancer. The abbot award lecture. Tumor Biol. 2008;29:161–80. doi:10.1159/000143402.

    Article  CAS  Google Scholar 

  59. Sell S, Leffert HL. An evaluation of cellular lineages in the pathogenesis of experimental hepatocellular carcinoma. Hepatology. 1982;2:77–86.

    Article  PubMed  CAS  Google Scholar 

  60. Sell S, Dunsford H. Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol. 1989;134:1347–63.

    PubMed  CAS  Google Scholar 

  61. Sell S, Leffert HL. Liver cancer stem cells. J Clin Oncol. 2008;26:2800–5.

    Article  PubMed  Google Scholar 

  62. Sell S. Stem cells in hepatocarcinogenesis. Cell Science Reviews. ISN NO. 2003;3:1742–8130.

    Google Scholar 

  63. Guest I, Ilic Z, Sell S. Age dependence of oval cell responses and bile duct carcinomas in male Fischer 344 rats fed a cyclic choline-deficient, ethionine-supplemented diet. Hepatology. 2010;52: 1750–7.

    Article  PubMed  CAS  Google Scholar 

  64. Korsching E, Jeffrey SS, et al. Basal carcinoma of the breast revisited: an old entity with new interpretations. J Clin Pathol. 2008;61:553–60.

    Article  PubMed  CAS  Google Scholar 

  65. Pott P. Chirurgical observations relative to the cataract, the polypus of the nose, the cancer of the scrotum, the different kinds of ruptures, and the mortification of the toes and feet. London: Hawes, Clarke and Collins; 1775.

    Google Scholar 

  66. Yamagiwa K, Ichikawa K. Experimental study of the pathogenesis of carcinoma. J Cancer Res. 1918;3:1–29.

    Google Scholar 

  67. Rous P, Kidd JG. Conditional neoplasms and subthreshold neoplastic states. J Exp Med. 1942;73:365–72.

    Article  Google Scholar 

  68. Berenblum I. The mechanism of carcinogenesis. A study of the significance of cocarcinogenic action and related phenomena. Cancer Res. 1941;1:807.

    CAS  Google Scholar 

  69. Boutwell RK. Some biological aspects of skin carcinogenesis. Prog Exp Tumor Res. 1964;4:207–50.

    PubMed  CAS  Google Scholar 

  70. Van Duuren BL, Sivak A, Katz C, Seidman I, Melchionne S. The effect of ageing and interval between primary and secondary treatment in two-stage carcinogenesis on mouse skin. Cancer Res. 1975;35:502–5.

    PubMed  Google Scholar 

  71. Potten CS, Morris RJ. Epithelial stem cells in vivo. J Cell Sci Suppl. 1988;10:45–62.

    Article  PubMed  CAS  Google Scholar 

  72. Nowell PC. Diagnostic and prognostic value of chromosome studies in cancer. Ann Clin Lab Sci. 1974;4:234–40.

    PubMed  CAS  Google Scholar 

  73. Rowley JD. Nonrandom chromosomal abnormalities in hematologic disorders of man. Proc Natl Acad Sci USA. 1975;72:152–6.

    Article  PubMed  CAS  Google Scholar 

  74. Chalandon Y, Schwaller J. Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies. Haematologica. 2005;90:949–68.

    PubMed  CAS  Google Scholar 

  75. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;1:702–3.

    Article  PubMed  CAS  Google Scholar 

  76. Cory S, Vaux DL, Harris AW, Adams JM. Insights from Bcl-2 and Myc: malignancy involves abrogation of apoptosis as well as sustained proliferation. Cancer Res. 1999;59(7 Suppl):1681s–92s.

    Google Scholar 

  77. Park SS, Kim JS, Tessarollo L, Owens JD, Peng L, Han SS, Tae Chung S, Torrey TA, Cheung WC, Plakiewica RD, McNeil N, Ried T, Buchinski JF, Morse 3rd HC, Janz S. Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. Cancer Res. 2005;65:1306–15.

    Article  PubMed  CAS  Google Scholar 

  78. Sell S. Leukemia: stem cells, maturation arrest and differentiation therapy. Stem Cell Rev. 2005;1:197–205.

    Article  PubMed  CAS  Google Scholar 

  79. Drucker BJ, Ralpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian J, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;334: 1031–7.

    Article  Google Scholar 

  80. Drucker BJ, Cuilhot F, O’Brien SG, et al. Five year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  Google Scholar 

  81. Melnick A, Licht JD. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999;93:3167–215.

    PubMed  CAS  Google Scholar 

  82. Soignet S, Fleischauer A, Pollyak T, Heller G, Warrel Jr RP. All trans retinoic acid significantly increases 5-year survival in patients with acute promyelocytic leukemia: long term follow-up of the New York study. Cancer Chemother Pharmacol. 1997;40: S24–9.

    Article  Google Scholar 

  83. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194:23–8.

    Article  PubMed  CAS  Google Scholar 

  84. Fowler JF. Radiation biology as applied to radiotherapy. Curr Top Radiat Res. 1966;2:304–64.

    Google Scholar 

  85. Trott KR. Tumour stem cells: the biological concept and its application in cancer treatment. Radiother Oncol. 1994;30:1–5.

    Article  PubMed  CAS  Google Scholar 

  86. Denekamp J. Tumour stem cells: facts, interpretation and consequences. Radiother Oncol. 1994;30:6–10.

    Article  PubMed  CAS  Google Scholar 

  87. Eric R, Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  Google Scholar 

  88. Zhang T, Otevrel T, Gao Z, Gao Z, Ehrlich SM, Fields JZ, Bowman BM. Evidence that APC regulates surviving expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res. 2001;62:8664–7.

    Google Scholar 

  89. Brittan M, Wright NA. Stem cell origin of cell lineages, proliferative units, and cancer in the gastrointestinal tract. In: Sell S, editor. Stem cell handbook. Totowa, NJ: Humana; 2004. p. 329.

    Google Scholar 

  90. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium. Clinical implications of multicentric origin. Cancer. 1953;6:963–8.

    Article  PubMed  CAS  Google Scholar 

  91. Carlson JA, Scott D, Wharton J, Sell S. Incidental histopathologic patterns: possible evidence of “field cancerization” surrounding skin tumors. Am J Dermatopathol. 2001;223:494–7.

    Article  Google Scholar 

  92. Braakhuis JMB, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63:1727–30.

    PubMed  CAS  Google Scholar 

  93. Ushijima T, Nakajima T, Maekita T. DNA methylation as a marker for the past and future. J Gastroenterol. 2006;41:401–7. doi:10.1007/s00535-006-1846-6.

    Article  PubMed  CAS  Google Scholar 

  94. Ushijima T. Epigenetic field for cancerization. J Biochem Mol Biol. 2007;40:142–50.

    Article  PubMed  CAS  Google Scholar 

  95. Ushijima T. Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer. 2005;5:223–31. doi:10.1038/nrc1571.

    Article  PubMed  CAS  Google Scholar 

  96. Godlblatt H, Cameron G. Induced malignancy in cells from rat myocardium subjected to intermittent anaerobiosis during long propagation in vitro. J Exp Med. 1953;97:525–62.

    Article  Google Scholar 

  97. Warberg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30. PMCID: PMC2140820.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Translational Medicine, New York State Department of Health, C405 Empire State Plaza, Albany, NY, 12201, USA

    Stewart Sell M.D.

  2. Occupational Health Department, Foundation for Research into the Biological Therapies of Cancer, Scientific Institute of Research and Health Care (IRCCS) Multimedica, Via S. Vittore 12 Milano, Via Milanese 300 Sesto S.G., 20123, Milan, Italy

    Pier Mario Biava M.D.

Authors
  1. Stewart Sell M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pier Mario Biava M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stewart Sell M.D. .

Editor information

Editors and Affiliations

  1. New York State Health Department Wadsworth Center, Albany, New York, USA

    Stewart Sell

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science + Business Media New York

About this chapter

Cite this chapter

Sell, S., Biava, P.M. (2013). Cancer Is a Problem of Developmental Biology: Maturation Arrest and the Hierarchical Model of the Origin of Cancer from Stem Cells. In: Sell, S. (eds) Stem Cells Handbook. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-7696-2_31

Download citation

Publish with us

Policies and ethics

Search

Navigation