Skip to main content

Advertisement

Log in

Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Genetic instability is invoked in explaining the cell phenotype changes that take place during cancer progression. However, the coexistence of a vast diversity of distinct clones, most prominently visible in the form of non-clonal chromosomal aberrations, suggests that Darwinian selection of mutant cells is not operating at maximal efficacy. Conversely, non-genetic instability of cancer cells must also be considered. Such mutation-independent instability of cell states is most prosaically manifest in the phenotypic heterogeneity within clonal cell populations or in the reversible switching between immature “cancer stem cell-like” and more differentiated states. How are genetic and non-genetic instability related to each other? Here, we review basic theoretical foundations and offer a dynamical systems perspective in which cancer is the inevitable pathological manifestation of modes of malfunction that are immanent to the complex gene regulatory network of the genome. We explain in an accessible, qualitative, and permissively simplified manner the mathematical basis for the “epigenetic landscape” and how the latter relates to the better known “fitness landscape.” We show that these two classical metaphors have a formal basis. By combining these two landscape concepts, we unite development and somatic evolution as the drivers of the relentless increase in malignancy. Herein, the cancer cells are pushed toward cancer attractors in the evolutionarily unused regions of the epigenetic landscape that encode more and more “dedifferentiated” states as a consequence of both genetic (mutagenic) and non-genetic (regulatory) perturbations—including therapy. This would explain why for the cancer cell, the principle of “What does not kill me makes me stronger” is as much a driving force in tumor progression and development of drug resistance as the simple principle of “survival of the fittest.”

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1998). Genetic instabilities in human cancers. Nature, 396(6712), 643–649.

    PubMed  CAS  Google Scholar 

  2. Cahill, D. P., Kinzler, K. W., Vogelstein, B., & Lengauer, C. (1999). Genetic instability and Darwinian selection in tumours. Trends in Cell Biology, 9(12), M57–M60.

    PubMed  CAS  Google Scholar 

  3. Attolini, C. S., & Michor, F. (2009). Evolutionary theory of cancer. Annals of the New York Academy of Sciences, 1168, 23–51. doi:10.1111/j.1749-6632.2009.04880.x (Review).

    PubMed  CAS  Google Scholar 

  4. Nowak, M. A., Michor, F., & Iwasa, Y. (2006). Genetic instability and clonal expansion. Journal of Theoretical Biology, 241(1), 26–32. doi:10.1016/j.jtbi.2005.11.012.

    PubMed  CAS  Google Scholar 

  5. Heng, H. H., Stevens, J. B., Bremer, S. W., Ye, K. J., Liu, G., & Ye, C. J. (2010). The evolutionary mechanism of cancer. Journal of Cellular Biochemistry, 109(6), 1072–1084. doi:10.1002/jcb.22497.

    PubMed  CAS  Google Scholar 

  6. McCullough, K. D., Coleman, W. B., Ricketts, S. L., Wilson, J. W., Smith, G. J., & Grisham, J. W. (1998). Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors. Proceedings of the National Academy of Sciences of the United States of America, 95(26), 15333–15338.

    PubMed  CAS  Google Scholar 

  7. Gupta, P. B., Fillmore, C. M., Jiang, G., Shapira, S. D., Tao, K., Kuperwasser, C., et al. (2011). Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell, 146(4), 633–644. doi:10.1016/j.cell.2011.07.026 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  8. Chaffer, C. L., Brueckmann, I., Scheel, C., Kaestli, A. J., Wiggins, P. A., Rodrigues, L. O., et al. (2011). Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proceedings of the National Academy of Sciences of the United States of America, 108(19), 7950–7955. doi:10.1073/pnas.1102454108.

    PubMed  CAS  Google Scholar 

  9. Roesch, A., Fukunaga-Kalabis, M., Schmidt, E. C., Zabierowski, S. E., Brafford, P. A., Vultur, A., et al. (2010). A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell, 141(4), 583–594. doi:10.1016/j.cell.2010.04.020.

    PubMed  CAS  Google Scholar 

  10. Dean, M., Fojo, T., & Bates, S. (2005). Tumour stem cells and drug resistance. Nature Reviews. Cancer, 5(4), 275–284.

    PubMed  CAS  Google Scholar 

  11. Hoek, K. S., & Goding, C. R. (2010). Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell & Melanoma Research, 23(6), 746–759. doi:10.1111/j.1755-148X.2010.00757.x (Comparative study review).

    CAS  Google Scholar 

  12. Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., et al. (2010). A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 141(1), 69–80. doi:10.1016/j.cell.2010.02.027.

    PubMed  CAS  Google Scholar 

  13. Huang, S. (2012). Tumor progression: chance and necessity in Darwinian and Lamarckian somatic (mutationless) evolution. Progress in Biophysics and Molecular Biology, 110(1), 69–86.

    PubMed  CAS  Google Scholar 

  14. Holmberg, J., & Perlmann, T. (2012). Maintaining differentiated cellular identity. Nature Reviews. Genetics, 13(6), 429–439. doi:10.1038/nrg3209 (Research support, non-U.S. government. Review).

    PubMed  CAS  Google Scholar 

  15. Sawyers, C. L., Denny, C. T., & Witte, O. N. (1991). Leukemia and the disruption of normal hematopoiesis. Cell, 64(2), 337–350 (Research support, non-U.S. government. Review).

    PubMed  CAS  Google Scholar 

  16. Virchow, R. L. K. (1978). Cellular pathology (1859th ed., pp. 204–207). London: John Churchill.

    Google Scholar 

  17. Deutscher, G. (2010). Through the language glass: why the world looks different in other languages (1st ed.). New York: Macmillan.

    Google Scholar 

  18. Huang, S. (2012). The molecular and mathematical basis of Waddington’s epigenetic landscape: a framework for post-Darwinian biology. BioEssays, 34(2), 149–155.

    PubMed  CAS  Google Scholar 

  19. Sieber, O., Heinimann, K., & Tomlinson, I. (2005). Genomic stability and tumorigenesis. Seminars in Cancer Biology, 15(1), 61–66. doi:10.1016/j.semcancer.2004.09.005.

    PubMed  CAS  Google Scholar 

  20. Negrini, S., Gorgoulis, V. G., & Halazonetis, T. D. (2010). Genomic instability—an evolving hallmark of cancer. Nature Reviews. Molecular Cell Biology, 11(3), 220–228. doi:10.1038/nrm2858.

    PubMed  CAS  Google Scholar 

  21. Beckman, R. A. (2010). Efficiency of carcinogenesis: is the mutator phenotype inevitable? Seminars in Cancer Biology, 20(5), 340–352. doi:10.1016/j.semcancer.2010.10.004 (Review).

    PubMed  CAS  Google Scholar 

  22. Bielas, J. H., & Loeb, L. A. (2005). Mutator phenotype in cancer: timing and perspectives. Environmental and Molecular Mutagenesis, 45(2–3), 206–213.

    PubMed  CAS  Google Scholar 

  23. Huang, S., & Ingber, D. E. (2000). Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks. Experimental Cell Research, 261(1), 91–103.

    PubMed  CAS  Google Scholar 

  24. Huang, S. (2009). Non-genetic heterogeneity of cells in development: more than just noise. Development, 136(23), 3853–3862. doi:10.1242/dev.035139.

    PubMed  CAS  Google Scholar 

  25. Altschuler, S. J., & Wu, L. F. (2010). Cellular heterogeneity: do differences make a difference? Cell, 141(4), 559–563. doi:10.1016/j.cell.2010.04.033.

    PubMed  CAS  Google Scholar 

  26. Stewart, J. M., Shaw, P. A., Gedye, C., Bernardini, M. Q., Neel, B. G., & Ailles, L. E. (2011). Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 108(16), 6468–6473. doi:10.1073/pnas.1005529108.

    PubMed  CAS  Google Scholar 

  27. Baum, B., Settleman, J., & Quinlan, M. P. (2008). Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol, 19(3), 294–308. doi:10.1016/j.semcdb.2008.02.001.

    PubMed  CAS  Google Scholar 

  28. Singh, A., & Settleman, J. (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene, 29(34), 4741–4751. doi:10.1038/onc.2010.215.

    PubMed  CAS  Google Scholar 

  29. Bonifer, C. (2005). Epigenetic plasticity of hematopoietic cells. Cell Cycle, 4(2), 211–214.

    PubMed  CAS  Google Scholar 

  30. Frisen, J. (2002). Stem cell plasticity? Neuron, 35(3), 415–418.

    PubMed  CAS  Google Scholar 

  31. Joshi, C. V., & Enver, T. (2002). Plasticity revisited. Current Opinion in Cell Biology, 14(6), 749–755.

    PubMed  CAS  Google Scholar 

  32. Raff, M. (2003). Adult stem cell plasticity: fact or artifact? Annual Review of Cell and Developmental Biology, 19, 1–22.

    PubMed  CAS  Google Scholar 

  33. Gotzmann, J., Mikula, M., Eger, A., Schulte-Hermann, R., Foisner, R., Beug, H., et al. (2004). Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutation Research, 566(1), 9–20.

    PubMed  CAS  Google Scholar 

  34. Spencer, S. L., Gerety, R. A., Pienta, K. J., & Forrest, S. (2006). Modeling somatic evolution in tumorigenesis. PLoS Computational Biology, 2(8), e108.

    PubMed  Google Scholar 

  35. Vogelstein, B., & Kinzler, K. W. (1993). The multistep nature of cancer. Trends in Genetics, 9(4), 138–141.

    PubMed  CAS  Google Scholar 

  36. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. doi:10.1016/j.cell.2011.02.013 (Research support, N.I.H. Extramural review).

    PubMed  CAS  Google Scholar 

  37. Huang, S. (2011). Systems biology of stem cells: three useful perspectives to help overcome the paradigm of linear pathways. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 366(1575), 2247–2259. doi:10.1098/rstb.2011.0008.

    PubMed  CAS  Google Scholar 

  38. Huang, S., & Kauffman, S. (2009). Complex gene regulatory networks—from structure to biological observables: cell fate determination. In R. A. Meyers (Ed.), Encyclopedia of complexity and systems science. Heidelberg: Springer, 1180–1213.

  39. Huang, S. (2009). Reprogramming cell fates: reconciling rarity with robustness. BioEssays, 31(5), 546–560. doi:10.1002/bies.200800189.

    PubMed  CAS  Google Scholar 

  40. Eldar, A., & Elowitz, M. B. (2010). Functional roles for noise in genetic circuits. Nature, 467(7312), 167–173. doi:10.1038/nature09326.

    PubMed  CAS  Google Scholar 

  41. Kaern, M., Elston, T. C., Blake, W. J., & Collins, J. J. (2005). Stochasticity in gene expression: from theories to phenotypes. Nature Reviews. Genetics, 6(6), 451–464.

    PubMed  CAS  Google Scholar 

  42. Raj, A., & van Oudenaarden, A. (2008). Nature, nurture, or chance: stochastic gene expression and its consequences. Cell, 135(2), 216–226. doi:10.1016/j.cell.2008.09.050.

    PubMed  CAS  Google Scholar 

  43. Huang, S. (2010). Cell lineage determination in state space: a systems view brings flexibility to dogmatic canonical rules. PLoS Biology, 8(5), e1000380. doi:10.1371/journal.pbio.1000380.

    PubMed  Google Scholar 

  44. Zhou, J. X., Aliyu, M. D., Aurell, E., & Huang, S. (2012). Quasi-potential landscape in complex multi-stable systems. Journal of the Royal Society, Interface, 9(77), 3539–3553. doi:10.1098/rsif.2012.0434.

    PubMed  Google Scholar 

  45. Ferrell, J. E., & Xiong, W. (2001). Bistability in cell signaling: how to make continuous processes discontinuous, and reversible processes irreversible. Chaos, 11(1), 227–236. doi:10.1063/1.1349894.

    PubMed  CAS  Google Scholar 

  46. Tyson, J. J., Chen, K. C., & Novak, B. (2003). Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Current Opinion in Cell Biology, 15(2), 221–231.

    PubMed  CAS  Google Scholar 

  47. Huang, S. (2001). Genomics, complexity and drug discovery: insights from Boolean network models of cellular regulation. Pharmacogenomics, 2(3), 203–222.

    PubMed  CAS  Google Scholar 

  48. Waddington, C. H. (1957). The strategy of the genes. London: Allen and Unwin.

    Google Scholar 

  49. Kauffman, S. (1969). Homeostasis and differentiation in random genetic control networks. Nature, 224(215), 177–178.

    PubMed  CAS  Google Scholar 

  50. Ptashne, M. (2007). On the use of the word ‘epigenetic’. Current Biology, 17(7), R233–R236.

    PubMed  CAS  Google Scholar 

  51. Bird, A. (2007). Perceptions of epigenetics. Nature, 447(7143), 396–398.

    PubMed  CAS  Google Scholar 

  52. Holliday, R. (2005). DNA methylation and epigenotypes. Biochemistry (Mosc), 70(5), 500–504.

    CAS  Google Scholar 

  53. Kouzarides, T. (2007). Chromatin modifications and their function. Cell, 128(4), 693–705.

    PubMed  CAS  Google Scholar 

  54. Kubicek, S., & Jenuwein, T. (2004). A crack in histone lysine methylation. Cell, 119(7), 903–906.

    PubMed  CAS  Google Scholar 

  55. Trojer, P., & Reinberg, D. (2006). Histone lysine demethylases and their impact on epigenetics. Cell, 125(2), 213–217.

    PubMed  CAS  Google Scholar 

  56. Bonifer, C., Hoogenkamp, M., Krysinska, H., & Tagoh, H. (2008). How transcription factors program chromatin—lessons from studies of the regulation of myeloid-specific genes. Seminars in Immunology, 20(4), 257–263. doi:10.1016/j.smim.2008.05.001.

    PubMed  CAS  Google Scholar 

  57. Suter, D. M., Molina, N., Naef, F., & Schibler, U. (2011). Origins and consequences of transcriptional discontinuity. Current Opinion in Cell Biology, 23(6), 657–662. doi:10.1016/j.ceb.2011.09.004.

    PubMed  CAS  Google Scholar 

  58. Lynch, M. (2007). Colloquium papers: the frailty of adaptive hypotheses for the origins of organismal complexity. Proceedings of the National Academy of Sciences of the United States of America, 104(Suppl 1), 8597–8604.

    PubMed  CAS  Google Scholar 

  59. Nowak, M. A. (2006). Evolutionary dynamics: exploring the equations of life (1st ed.). Cambridge, MA: Belknap.

  60. Wright, S. (1945). The differential equation of the distribution of gene frequencies. Proceedings of the National Academy of Sciences of the United States of America, 31(12), 382–389.

    PubMed  CAS  Google Scholar 

  61. Kauffman, S. A. (1993). The origins of order. New York: Oxford University Press.

    Google Scholar 

  62. Galhardo, R. S., Hastings, P. J., & Rosenberg, S. M. (2007). Mutation as a stress response and the regulation of evolvability. Critical Reviews in Biochemistry and Molecular Biology, 42(5), 399–435. doi:10.1080/10409230701648502 (Research support, N.I.H. Extramural review).

    PubMed  CAS  Google Scholar 

  63. Brutovsky, B., & Horvath, D. (2010). Optimization aspects of carcinogenesis. Medical Hypotheses, 74(5), 922–927. doi:10.1016/j.mehy.2009.10.019 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  64. Bielas, J. H., Loeb, K. R., Rubin, B. P., True, L. D., & Loeb, L. A. (2006). Human cancers express a mutator phenotype. Proceedings of the National Academy of Sciences of the United States of America, 103(48), 18238–18242.

    PubMed  CAS  Google Scholar 

  65. Cairns, J. (1975). Mutation selection and the natural history of cancer. Nature, 255(5505), 197–200.

    PubMed  CAS  Google Scholar 

  66. Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews. Cancer, 9(4), 302–312. doi:10.1038/nrc2627.

    PubMed  CAS  Google Scholar 

  67. Bernards, R., & Weinberg, R. A. (2002). A progression puzzle. Nature, 418(6900), 823.

    PubMed  CAS  Google Scholar 

  68. Brock, A., Chang, H., & Huang, S. (2009). Non-genetic heterogeneity—a mutation-independent driving force for the somatic evolution of tumours. Nature Reviews. Genetics, 10(5), 336–342. doi:10.1038/nrg2556.

    PubMed  CAS  Google Scholar 

  69. Gould, S. J. (1997). Darwinian fundamentalism. New York Review of Books (June 12), pp. 34–37.

  70. Gould, S. J., & Lewontin, R. C. (1979). The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proceedings of the Royal Society of London. Series B: Biological Sciences, 205(1161), 581–598.

    CAS  Google Scholar 

  71. Lewontin, R. C. (2000). The triple helix: gene, organism, and environment (2001st ed.). Cambridge, MA: Harvard University Press.

    Google Scholar 

  72. Rose, S., Kamin, L. J., & Lewontin, R. C. (1985). Not in our genes: biology, ideology, and human nature. New York: Pantheon.

    Google Scholar 

  73. Pigliucci, M. (2009). An extended synthesis for evolutionary biology. Annals of the New York Academy of Sciences, 1168, 218–228. doi:10.1111/j.1749-6632.2009.04578.x.

    PubMed  Google Scholar 

  74. Noble, D. (2011). Neo-Darwinism, the modern synthesis and selfish genes: are they of use in physiology? The Journal of Physiology, 589(Pt 5), 1007–1015. doi:10.1113/jphysiol.2010.201384 (Research support, non-U.S. government. Review).

    PubMed  CAS  Google Scholar 

  75. Eldredge, N., & Gould, S. J. (1997). On punctuated equilibria. Science, 276(5311), 338–341 (Comment letter).

    PubMed  CAS  Google Scholar 

  76. Caporale, L. H. (2009). Putting together the pieces: evolutionary mechanisms at work within genomes: can we suggest molecular underpinnings of punctuated equilibria and the Cambrian explosion? BioEssays, 31(7), 700–702. doi:10.1002/bies.200900067.

    PubMed  CAS  Google Scholar 

  77. Gould, S. J. (1994). Tempo and mode in the macroevolutionary reconstruction of Darwinism. Proceedings of the National Academy of Sciences of the United States of America, 91(15), 6764–6771 (Review).

    PubMed  CAS  Google Scholar 

  78. Heng, H. H., Bremer, S. W., Stevens, J., Ye, K. J., Miller, F., Liu, G., et al. (2006). Cancer progression by non-clonal chromosome aberrations. Journal of Cellular Biochemistry, 98(6), 1424–1435. doi:10.1002/jcb.20964 (Comparative study. Research support, non-U.S. government. Review).

    PubMed  CAS  Google Scholar 

  79. Heng, H. H., Stevens, J. B., Bremer, S. W., Liu, G., Abdallah, B. Y., & Ye, C. J. (2011). Evolutionary mechanisms and diversity in cancer. Advances in Cancer Research, 112, 217–253. doi:10.1016/B978-0-12-387688-1.00008-9 (Research support, non-U.S. government, non-P.H.S. Review).

    PubMed  CAS  Google Scholar 

  80. Stephens, P. J., Greenman, C. D., Fu, B., Yang, F., Bignell, G. R., Mudie, L. J., et al. (2011). Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell, 144(1), 27–40. doi:10.1016/j.cell.2010.11.055.

    PubMed  CAS  Google Scholar 

  81. Huang, S., Ernberg, I., & Kauffman, S. (2009). Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Seminars in Cell & Developmental Biology, 20(7), 869–876. doi:10.1016/j.semcdb.2009.07.003.

    CAS  Google Scholar 

  82. Davies, P. C., & Lineweaver, C. H. (2011). Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Physical Biology, 8((1), 015001. doi:10.1088/1478-3975/8/1/015001 (Research support, N.I.H., Extramural).

    Google Scholar 

  83. Ben-Jacob, E., Coffey, D. S., & Levine, H. (2012). Bacterial survival strategies suggest rethinking cancer cooperativity. Trends in Microbiology, 20(9), 403–410. doi:10.1016/j.tim.2012.06.001.

    PubMed  CAS  Google Scholar 

  84. Kauffman, S. (1971). Differentiation of malignant to benign cells. Journal of Theoretical Biology, 31(3), 429–451.

    PubMed  CAS  Google Scholar 

  85. Huang, S. (2011). On the intrinsic inevitability of cancer: from foetal to fatal attraction. Seminars in Cancer Biology, 21(3), 183–199. doi:10.1016/j.semcancer.2011.05.003.

    PubMed  Google Scholar 

  86. Aldana, M., Balleza, E., Kauffman, S., & Resendiz, O. (2007). Robustness and evolvability in genetic regulatory networks. Journal of Theoretical Biology, 245(3), 433–448.

    PubMed  Google Scholar 

  87. Torres-Sosa, C., Huang, S., & Aldana, M. (2012). Criticality is an emergent property of genetic networks that exhibit evolvability. PLoS Computational Biology, 8(9), e1002669. doi:10.1371/journal.pcbi.1002669 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  88. Sonnenschein, C., & Soto, A. M. (1998). The society of cells: cancer and control of cell proliferation. Philadelphia, PA: Garland Science.

  89. Raff, M. C. (1992). Social controls on cell survival and cell death. Nature, 356(6368), 397–400.

    PubMed  CAS  Google Scholar 

  90. Paulovich, A. G., Toczyski, D. P., & Hartwell, L. H. (1997). When checkpoints fail. Cell, 88(3), 315–321.

    PubMed  CAS  Google Scholar 

  91. Hernando, E., Nahle, Z., Juan, G., Diaz-Rodriguez, E., Alaminos, M., Hemann, M., et al. (2004). Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature, 430(7001), 797–802.

    PubMed  CAS  Google Scholar 

  92. Mantel, C., Guo, Y., Lee, M. R., Kim, M. K., Han, M. K., Shibayama, H., et al. (2007). Checkpoint–apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability. Blood, 109(10), 4518–4527. doi:10.1182/blood-2006-10-054247 (Research support, N.I.H., non-U.S. government. Extramural).

    PubMed  CAS  Google Scholar 

  93. Erenpreisa, J., & Cragg, M. S. (2007). Cancer: a matter of life cycle? Cell Biology International, 31(12), 1507–1510. doi:10.1016/j.cellbi.2007.08.013 (Review).

    PubMed  CAS  Google Scholar 

  94. Balleza, E., Alvarez-Buylla, E. R., Chaos, A., Kauffman, A., Shmulevich, I., & Aldana, M. (2008). Critical dynamics in genetic regulatory networks: examples from four kingdoms. PLoS One, 3, e2456.

    PubMed  Google Scholar 

  95. Shmulevich, I., Kauffman, S. A., & Aldana, M. (2005). Eukaryotic cells are dynamically ordered or critical but not chaotic. Proceedings of the National Academy of Sciences of the United States of America, 102(38), 13439–13444.

    PubMed  CAS  Google Scholar 

  96. Mitsiadis, T. A., Caton, J., & Cobourne, M. (2006). Waking-up the sleeping beauty: recovery of the ancestral bird odontogenic program. Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution, 306(3), 227–233. doi:10.1002/jez.b.21094 (Research support, non-U.S. government. Comparative study).

    PubMed  Google Scholar 

  97. Newman, S. A. (2011). Thermogenesis, muscle hyperplasia, and the origin of birds. BioEssays, 33(9), 653–656. doi:10.1002/bies.201100061 (Research support, U.S. government, non-P.H.S.).

    PubMed  Google Scholar 

  98. Kitada, K., Taima, A., Ogasawara, K., Metsugi, S., & Aikawa, S. (2011). Chromosome-specific segmentation revealed by structural analysis of individually isolated chromosomes. Genes, Chromosomes & Cancer, 50(4), 217–227. doi:10.1002/gcc.20847.

    CAS  Google Scholar 

  99. Li, R., Yerganian, G., Duesberg, P., Kraemer, A., Willer, A., Rausch, C., et al. (1997). Aneuploidy correlated 100 % with chemical transformation of Chinese hamster cells. Proceedings of the National Academy of Sciences of the United States of America, 94(26), 14506–14511.

    PubMed  CAS  Google Scholar 

  100. Clark, W. H. (1991). Tumour progression and the nature of cancer. British Journal of Cancer, 64(4), 631–644.

    PubMed  CAS  Google Scholar 

  101. Mitchison, T. J. (2012). The proliferation rate paradox in antimitotic chemotherapy. Molecular Biology of the Cell, 23(1), 1–6. doi:10.1091/mbc.E10-04-0335 (Research support, N.I.H. Extramural).

    PubMed  CAS  Google Scholar 

  102. Persons, D. L., Yazlovitskaya, E. M., Cui, W., & Pelling, J. C. (1999). Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. Clinical Cancer Research, 5(5), 1007–1014 (Research support, U.S. government, P.H.S. Comparative study).

    PubMed  CAS  Google Scholar 

  103. Sims, A. H., Zweemer, A. J., Nagumo, Y., Faratian, D., Muir, M., Dodds, M., et al. (2012). Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer. British Journal of Cancer, 106(11), 1779–1789. doi:10.1038/bjc.2012.176 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  104. Levsky, J. M., & Singer, R. H. (2003). Gene expression and the myth of the average cell. Trends in Cell Biology, 13(1), 4–6.

    PubMed  CAS  Google Scholar 

  105. Chang, H. H., Hemberg, M., Barahona, M., Ingber, D. E., & Huang, S. (2008). Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature, 453(7194), 544–547.

    PubMed  CAS  Google Scholar 

  106. Cohen, A. A., Geva-Zatorsky, N., Eden, E., Frenkel-Morgenstern, M., Issaeva, I., Sigal, A., et al. (2008). Dynamic proteomics of individual cancer cells in response to a drug. Science, 322, 1511–1516.

    Google Scholar 

  107. Spencer, S. L., Gaudet, S., Albeck, J. G., Burke, J. M., & Sorger, P. K. (2009). Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature, 459(7245), 428–432. doi:10.1038/nature08012.

    PubMed  CAS  Google Scholar 

  108. Darwin, C. (1869). On the origin of species by means of natural selection, or the preservation of favoured races in the struggle for life (5th ed., pp. 91–92). London: John Murray.

    Google Scholar 

  109. Nietzsche, F. (1998). Twilight of the idols (D. Large, trans.). Oxford: Oxford University Press.

    Google Scholar 

  110. Dirks, P. (2010). Cancer stem cells: invitation to a second round. Nature, 466(7302), 40–41. doi:10.1038/466040a.

    PubMed  CAS  Google Scholar 

  111. Gupta, P. B., Chaffer, C. L., & Weinberg, R. A. (2009). Cancer stem cells: mirage or reality? Nature Medicine, 15(9), 1010–1012. doi:10.1038/nm0909-1010.

    PubMed  CAS  Google Scholar 

  112. Hill, R. P., & Perris, R. (2007). “Destemming” cancer stem cells. Journal of the National Cancer Institute, 99(19), 1435–1440.

    PubMed  CAS  Google Scholar 

  113. Jordan, C. T. (2009). Cancer stem cells: controversial or just misunderstood? Cell Stem Cell, 4(3), 203–205. doi:10.1016/j.stem.2009.02.003.

    PubMed  CAS  Google Scholar 

  114. Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L., & Strasser, A. (2007). Tumor growth need not be driven by rare cancer stem cells. Science, 317(5836), 337. doi:10.1126/science.1142596.

    PubMed  CAS  Google Scholar 

  115. Lobo, N. A., Shimono, Y., Qian, D., & Clarke, M. F. (2007). The biology of cancer stem cells. Annual Review of Cell and Developmental Biology, 23, 675–699. doi:10.1146/annurev.cellbio.22.010305.104154.

    PubMed  CAS  Google Scholar 

  116. Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111.

    PubMed  CAS  Google Scholar 

  117. Blick, T., Widodo, E., Hugo, H., Waltham, M., Lenburg, M. E., Neve, R. M., et al. (2008). Epithelial mesenchymal transition traits in human breast cancer cell lines. Clinical & Experimental Metastasis, 25(6), 629–642.

    CAS  Google Scholar 

  118. Deka, J., Wiedemann, N., Anderle, P., Murphy-Seiler, F., Bultinck, J., Eyckerman, S., et al. (2010). Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas. Cancer Research, 70(16), 6619–6628. doi:10.1158/0008-5472.CAN-10-0148.

    PubMed  CAS  Google Scholar 

  119. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704–715.

    PubMed  CAS  Google Scholar 

  120. Donnenberg, V. S., & Donnenberg, A. D. (2005). Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. The Journal of Clinical Pharmacology, 45(8), 872–877.

    CAS  Google Scholar 

  121. Elliot, A., Adams, J., & Al-Hajj, M. (2010). The ABCs of cancer stem cell drug resistance. IDrugs, 13(9), 632–635.

    PubMed  Google Scholar 

  122. Lee, G. Y., Shim, J. S., Cho, B., Jung, J. Y., Lee, D. S., & Oh, I. H. (2011). Stochastic acquisition of a stem cell-like state and drug tolerance in leukemia cells stressed by radiation. International Journal of Hematology, 93(1), 27–35. doi:10.1007/s12185-010-0734-2 (Research support, non-U.S. government).

    PubMed  Google Scholar 

  123. Ghisolfi, L., Keates, A. C., Hu, X., Lee, D. K., & Li, C. J. (2012). Ionizing radiation induces stemness in cancer cells. PLoS One, 7(8), e43628. doi:10.1371/journal.pone.0043628 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  124. Andarawewa, K. L., Erickson, A. C., Chou, W. S., Costes, S. V., Gascard, P., Mott, J. D., et al. (2007). Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor beta induced epithelial to mesenchymal transition. Cancer Research, 67(18), 8662–8670. doi:10.1158/0008-5472.CAN-07-1294 (Research support, U.S. government, non-P.H.S.).

    PubMed  CAS  Google Scholar 

  125. Arumugam, T., Ramachandran, V., Fournier, K. F., Wang, H., Marquis, L., Abbruzzese, J. L., et al. (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Research, 69(14), 5820–5828. doi:10.1158/0008-5472.CAN-08-2819.

    PubMed  CAS  Google Scholar 

  126. Li, Q. Q., Xu, J. D., Wang, W. J., Cao, X. X., Chen, Q., Tang, F., et al. (2009). Twist1-mediated adriamycin-induced epithelial–mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clinical Cancer Research, 15(8), 2657–2665. doi:10.1158/1078-0432.CCR-08-2372 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  127. Li, Q. Q., Chen, Z. Q., Cao, X. X., Xu, J. D., Xu, J. W., Chen, Y. Y., et al. (2011). Involvement of NF-kappaB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial–mesenchymal transition of breast cancer cells. Cell Death and Differentiation, 18(1), 16–25. doi:10.1038/cdd.2010.103 (Research support, non-U.S. government).

    PubMed  Google Scholar 

  128. Wang, Z., Li, Y., Kong, D., Banerjee, S., Ahmad, A., Azmi, A. S., et al. (2009). Acquisition of epithelial–mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Research, 69(6), 2400–2407. doi:10.1158/0008-5472.CAN-08-4312 (Research support, N.I.H., non-U.S. government. Extramural).

    PubMed  CAS  Google Scholar 

  129. Chaudhary, P. M., & Roninson, I. B. (1993). Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. Journal of the National Cancer Institute, 85(8), 632–639.

    PubMed  CAS  Google Scholar 

  130. Abolhoda, A., Wilson, A. E., Ross, H., Danenberg, P. V., Burt, M., & Scotto, K. W. (1999). Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clinical Cancer Research, 5(11), 3352–3356.

    PubMed  CAS  Google Scholar 

  131. Stein, U., Jurchott, K., Walther, W., Bergmann, S., Schlag, P. M., & Royer, H. D. (2001). Hyperthermia-induced nuclear translocation of transcription factor YB-1 leads to enhanced expression of multidrug resistance-related ABC transporters. The Journal of Biological Chemistry, 276(30), 28562–28569. doi:10.1074/jbc.M100311200 (Research support, non-U.S. government).

    PubMed  CAS  Google Scholar 

  132. Chin, K. V., Tanaka, S., Darlington, G., Pastan, I., & Gottesman, M. M. (1990). Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. The Journal of Biological Chemistry, 265(1), 221–226.

    PubMed  CAS  Google Scholar 

  133. Pleasance, E. D., Cheetham, R. K., Stephens, P. J., McBride, D. J., Humphray, S. J., Greenman, C. D., et al. (2010). A comprehensive catalogue of somatic mutations from a human cancer genome. Nature, 463(7278), 191–196. doi:10.1038/nature08658.

    PubMed  CAS  Google Scholar 

  134. Yates, L. R., & Campbell, P. J. (2012). Evolution of the cancer genome. Nature Reviews. Genetics, 13(11), 795–806. doi:10.1038/nrg3317.

    PubMed  CAS  Google Scholar 

  135. Kreso, A., O'Brien, C. A., van Galen, P., Gan, O. I., Notta, F., Brown, A. M., et al. (2013). Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science, 339(6119), 543–548. doi:10.1126/science.1227670.

    PubMed  CAS  Google Scholar 

  136. Nobili, S., Landini, I., Mazzei, T., & Mini, E. (2012). Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Medicinal Research Reviews, 32, 1220–1262. doi:10.1002/med.20239.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author would like to thank the Institute for Systems Biology and Alberta Innovates for supporting this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sui Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, S. Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells. Cancer Metastasis Rev 32, 423–448 (2013). https://doi.org/10.1007/s10555-013-9435-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-013-9435-7

Keywords

Navigation