Modeling Cancer as A Complex Adaptive System: Genetic Instability and Evolution

  • Kenneth J. PientaEmail author
Part of the Topics in Biomedical Engineering International Book Series book series (ITBE)


Cancer is the second leading cause of death in the United States, claiming over 500,000 lives annually. While we now understand that cancer is a disease of genetic mutation, it is still difficult to describe how cancer arises from normal cells. Describing carcinogenesis in terms of a complex adaptive system reacting to the forces of Darwinian evolution gives a framework to understand tumorigenesis. This understanding is leading to new paradigms of cancer therapy, including multidisciplinary approaches to attack the cancer as a heterogeneous group of diseases as well as the development of aptamer molecular evolution techniques to design therapeutics to evolve as the cancer mutates.


Cancer Cell Vascular Endothelial Growth Factor Modeling Cancer Genetic Instability Boolean Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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6. References

  1. 1.
    Radman M, Matic I, Taddei F. 1999. Evolution of evolvability. Ann NY Acad Sci 870:146–155.PubMedCrossRefGoogle Scholar
  2. 2.
    Greaves M. 2002. Cancer causation: the Darwinian downside of past success? Lancet Oncol 3:244–251.PubMedCrossRefGoogle Scholar
  3. 3.
    Nowell PC. 1976. The clonal evolution of tumor cell populations. Science 194:23–28.PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100:57–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Nesse RM, Williams GC. 1998. Evolution and the origins of disease. Sci Am 279:58–65.CrossRefGoogle Scholar
  6. 6.
    Schwab ED, Pienta KJ. 1996. Cancer as a complex adaptive system. Med Hypotheses 47:235–241.PubMedCrossRefGoogle Scholar
  7. 7.
    Coffey DS. 2001. Similarities of prostate and breast cancer: evolution, diet, and estrogens. Urology 57:31–38.PubMedCrossRefGoogle Scholar
  8. 8.
    Pathak SK, Sharma, RA, Mellon JK. 2003. Chemoprevention of prostate cancer by diet-derived antioxidant agents and hormonal manipulation [review]. Int J Oncol 22:5–13.PubMedGoogle Scholar
  9. 9.
    Farinati F, Cardin R, Della Libera G, Herszenyi L, Marafin C, Molari A, Plebani M, Rugge M, Naccarato R. 1994. The role of anti-oxidants in the chemoprevention of gastric cancer. Eur J Cancer Prev 3(suppl 2):93–97.PubMedCrossRefGoogle Scholar
  10. 10.
    Taddei F, Radman M, Maynard-Smith J, Toupance B, Gouyon PH, Godelle B. 1997. Role of mutators in adaptive evolution. Nature 387:700–702.PubMedCrossRefGoogle Scholar
  11. 11.
    Marusic M. 1991. Evolutionary and biological foundations of malignant tumors. Med Hypotheses 34:282–287.PubMedCrossRefGoogle Scholar
  12. 12.
    Pienta KJ, Partin AW, Coffey DS. 1989. Cancer as a disease of DNA organization and dynamic cell structure. Cancer Res 49:2525–2532.PubMedGoogle Scholar
  13. 13.
    Neumann AA, Reddel RR. 2002. Telomere maintenance and cancer—look, no telomerase. Natl Rev Cancer 2:879–884.CrossRefGoogle Scholar
  14. 14.
    Rubin H. 20:6. 2002. The disparity between human cell senescence in vitro and lifelong replication in vivo. Nature Biotechnol 20:75–81.CrossRefGoogle Scholar
  15. 15.
    Pienta KJ, Ward WS. 1994. An unstable nuclear matrix may contribute to genetic instability. Med Hypotheses 42:45–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih Ie M, Vogelstein B, Lengauer C. 2002. The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA 99:16226–16231.PubMedCrossRefGoogle Scholar
  17. 17.
    Anderson GR, Stoler DL, Brenner BM. 2001. Cancer: the evolved consequence of a destabilized genome. Bioessays 23:1037–1046.PubMedCrossRefGoogle Scholar
  18. 18.
    Hoglund M, Gisselsson D, Sall T, Mitelman F. 2002. Coping with complexity: multivariate analysis of tumor karyotypes. Cancer Genet Cytogenet 135:103–109.PubMedCrossRefGoogle Scholar
  19. 19.
    Kerbel RS, Cornil I, Korczak, B. 1989. New insights into the evolutionary growth of tumors revealed by southern gel analysis of tumors genetically tagged with plasmid or proviral DNA insertions. J Cell Sci 94:381–387.PubMedGoogle Scholar
  20. 20.
    MacPhee DG. 1991. The significance of deletions in spontaneous and induced mutations associated with movement of transposable DNA elements: possible implications for evolution and cancer. Mutation Res 250:35–47.PubMedGoogle Scholar
  21. 21.
    Yuan J, Narayanan L, Rockwell S, Glazer PM. 2000. Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Res 60:4372–4376.PubMedGoogle Scholar
  22. 22.
    Reynolds TY, Rockwell S, Glazer PM. 1996. Genetic instability induced by the tumor microenvironment. Cancer Res 56:5754–5757.PubMedGoogle Scholar
  23. 23.
    Coffey DS, Isaacs JT. 1981. Prostate tumor biology and cell kinetics-theory. Urology 17(suppl):40–53.PubMedGoogle Scholar
  24. 24.
    Hussein MR, Haemel AK, Wood GS. 2003. Apoptosis and melanoma: molecular mechanisms. J Pathol 199:275–288.PubMedCrossRefGoogle Scholar
  25. 25.
    Bowen AR, Hanks AN, Allen SM, Alexander A, Diedrich MJ, Grossman D. 2003. Apoptosis regulators and responses in human melanocytic and keratinocytic cells. J Invest Dermatol 120:18–55.CrossRefGoogle Scholar
  26. 26.
    Hoglund M, Gisselsson D, Hansen GB, Sall T, Mitelman F. 2002. Multivariate analysis of chromosomal imbalances in breast cancer delineates cytogenetic pathways and reveals complex relationships among imbalances. Cancer Res 62:2675–2680.PubMedGoogle Scholar
  27. 27.
    Abraham S, Zhang W, Greenberg N, Zhang M. 2003. Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells. J Urol 169:1157–1161.PubMedCrossRefGoogle Scholar
  28. 28.
    Su ZZ, Gopalkrishnan RV, Narayan G, Dent P, Fisher PB. 2002. Progression elevated gene-3, PEG-3, induces genomic instability in rodent and human tumor cells. J Cell Physiol 192:34–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Kondoh N, Shuda M, Arai M, Oikawa T, Yamamoto M. 1988. Activation of anchorage-independent growth of HT1080 human fibroblasts. Mutat Res 199:273–291.Google Scholar
  30. 30.
    Cooper CR, Chay CH, Gendernalik JD, Lee HL, Bhatia J, Taichman RS, McCauley LK, Keller ET, Pienta KJ. 2003. Stromal factors involved in prostate carcinoma metastasis to bone. Cancer 97:739–747.PubMedCrossRefGoogle Scholar
  31. 31.
    Folkman J. 2002. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18.PubMedGoogle Scholar
  32. 32.
    van Nieuw Amerongen GP, Koolwijk P, Versteilen A, van Hinsbergh VW. 2003. Involvement of RhoA/Rho kinase signaling in VEGF-induced endothelial cell migration and angiogenesis in vitro. Arterioscler Thromb Vasc Biol 23:211–217.PubMedCrossRefGoogle Scholar
  33. 33.
    Chang L, Kaipainen A, Folkman J. 2002. Lymphangiogenesis new mechanisms. Ann NY Acad Sci 979:111–119.PubMedCrossRefGoogle Scholar
  34. 34.
    Chung AS, Yoon SO, Park SJ, Yun CH. 2003. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol 36(1):128–137.PubMedGoogle Scholar
  35. 35.
    Nambu Y, Beer DG. 2003. Altered surface markers in lung cancer: lack of cell-surface Fas/APO-1 expression in pulmonary adenocarcinoma may allow escape from immune surveillance. Methods Mol Med 74:259–266.PubMedGoogle Scholar
  36. 36.
    Ivanovic VV, Todorovic-Rakovic N, Demajo M, Neskovic-Konstantinovic Z, Subota V, Ivanisevic-Milovanovic O, Nikolic-Vukosavljevic D. 2002. Elevated plasma levels of transforming growth factor-beta(1) (TGF-beta(1)) in patients with advanced breast cancer: association with disease progression. Eur J Cancer 39:454–461.CrossRefGoogle Scholar
  37. 37.
    Keller ET, Zhang J, Cooper CR, Smith PC, McCauley LK, Pienta KJ, Taichman RS. 2001. Prostate carcinoma skeletal metastases: cross-talk between tumor and bone. Cancer Metastasis Rev 20:333–349.PubMedCrossRefGoogle Scholar
  38. 38.
    Rossi MC, Zetter BR. 1992. Selective stimulation of prostatic carcinoma cell proliferation by transferrin. Proc Natl Acad Sci USA 89:6197–6201.PubMedCrossRefGoogle Scholar
  39. 39.
    Schwab ED, Pienta KJ. 1997. Modeling signal transduction in normal and cancer cells using complex adaptive systems. Med Hypotheses 48:111–123.PubMedCrossRefGoogle Scholar
  40. 40.
    Holland J. 1995. Hidden order: how adaptation builds complexity. Addison-Wesley, New York.Google Scholar
  41. 41.
    Chinnaiyan AM, Coffey DS, Forrest S, Goldberg E, Holland J, Kepler T, Maley C, Mitchell M, Montie JE, Morowitz M, Nelson WG, Omenn G, Perelson AS, Pienta KJ, Rubin MA, Scardino P, Shapiro JA, Wheeler T. 2002. Merging bottom-up and top-down approaches to study prostate cancer biology. Complexity 7:22–30.CrossRefGoogle Scholar
  42. 42.
    Kauffman SA. 1991. Antichaos and adaptation. Sci Am 265:78–84.PubMedCrossRefGoogle Scholar
  43. 43.
    Pienta KJ, Murphy BC, Getzenberg RH, Coffey DS. 1993. The tissue matrix and the regulation of gene expression in cancer cells. Adv Mol Cell Biol 7:131–156.CrossRefGoogle Scholar
  44. 44.
    Temin HM. 1988. Evolution of cancer genes as a mutation-driven process. Cancer Res 48:1697–1701.PubMedGoogle Scholar
  45. 45.
    Lewin RS. 1993. Complexity: life at the edge of chaos. Collier Books, New York.Google Scholar
  46. 46.
    Bao JZ, Davis CC, Schmukler RE. 1993. Impedance spectroscopy of human erythrocytes: system calibration and nonlinear modeling. IEEE Trans Biomed Eng 40:364–378.PubMedCrossRefGoogle Scholar
  47. 47.
    Semenza GL. 2003. Targeting HIF-1 for cancer therapy. Nature Rev Cancer. 3:721–732.CrossRefGoogle Scholar
  48. 48.
    Kerr RA. 2002. Evolution: a trigger for the Cambrian explosion? Science 298:1547.PubMedCrossRefGoogle Scholar
  49. 49.
    Lupold SE, Hicke BJ, Lin Y, Coffey DS. 2002. Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res 62:4029–4033.PubMedGoogle Scholar
  50. 50.
    Coffey DS. 2002. Understanding the cancer biology universe: enigmas, context and future prospects. Cancer Biol Ther 1:564–567.PubMedGoogle Scholar
  51. 51.
    Faria M, Ulrich H. 2002. The use of synthetic oligonucleotides as protein inhibitors and anti-code drugs in cancer therapy: accomplishments and limitations. Curr Cancer Drug Targets 2:355–368.PubMedCrossRefGoogle Scholar
  52. 52.
    Cerchia L, Hamm J, Libri D, Tavitian B, de Franciscis V. 2002. Nucleic acid aptamers in cancer medicine. FEBS Lett 528:12–16.PubMedCrossRefGoogle Scholar
  53. 53.
    Lato SM, Ozerova ND, He K, Sergueeva Z, Shaw BR, Burke DH. 2002. Boron-containing aptamers to ATP. Nucleic Acids Res 30:1401–1407.PubMedCrossRefGoogle Scholar
  54. 54.
    Tuerk C, Gold L. 1990. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249(4968):505–510.PubMedCrossRefGoogle Scholar
  55. 55.
    Hicke BJ, Marion C, Chang YF, Gould T, Lynott CK, Parma D, Schmidt PG, Warren S. 2001. Tenascin-C aptamers are generated using tumor cells and purified protein. J Biol Chem 276:48644–48654.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Inc. 2006

Authors and Affiliations

  1. 1.University of Michigan Comprehensive Cancer CenterAnn Arbor

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