Cell-Cell Interactions in Solid Tumors — the Role of Cancer Stem Cells

  • Xuefeng Gao
  • J. Tyson McDonald
  • Lynn Hlatky
  • Heiko Enderling
Part of the SIMAI Springer Series book series (SEMA SIMAI)

Abstract

It is increasingly argued that solid tumors follow a cellular hierarchy comparable to normal tissues, with so-called cancer stem cells on top of the hierarchy. In this model, cancer stem cells have the unique capability to initiate and propagate solid tumors. Non-stem cancer cells will form the bulk of the tumor population, but are by themselves incapable of giving rise to a continuously growing tumor. The two distinct phenotypes interact with one another and compete for common resources such as oxygen, nutrients, or available space. Single cell kinetics are parameterized with in vitro data and the interplay between cancer stem cells and their non-stem cancer cell counterpart is studied using two different modeling approaches: a cellular automaton model and a cellular Potts model. Simulations of tumor growth with both techniques reveal that cancer stem cell-driven solid tumors grow as conglomerates of self-metastases, suggesting a robust biological phenomenon. The growth rate of the tumor is dependent on the complex interplay of the underlying model parameters.

References

  1. 1.
    Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., Clarke, M.F.: Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003)CrossRefGoogle Scholar
  2. 2.
    Alarcón, T., Byrne, H.M., Maini, P.K.: A cellular automaton model for tumour growth in inhomogeneous environment. J. Theor. Biol. 225, 257–274 (2003)CrossRefGoogle Scholar
  3. 3.
    Almog, N., Ma, L., Raychowdhury, R., Schwager, C., Erber, R., Short, S., Hlatky, L., Vajkoczy, P., Huber, P.E., Folkman, J., Abdollahi, A.: Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 69, 836–844 (2009)CrossRefGoogle Scholar
  4. 4.
    Anderson, A.R.A.: A hybrid mathematical model of solid tumour invasion: the importance of cell adhesion. Math. Med. Biol. 22, 163–186 (2005)CrossRefMATHGoogle Scholar
  5. 5.
    Basanta, D., Hatzikirou, H., Deutsch, A.: Studying the emergence of invasiveness in tumours using game theory. Eur. Phys. J. B 63, 393–397 (2008)CrossRefMATHGoogle Scholar
  6. 6.
    Cipra, B.: An introduction to the Ising model. Am. Math. Monthly 94, 937–959 (1987)CrossRefGoogle Scholar
  7. 7.
    Dewri, R., Chakraborti, N.: (2005) Simulating recrystallization through cellular automata and genetic algorithms. Modelling Simul. Mater. Sci. Eng. 13, 173–183CrossRefGoogle Scholar
  8. 8.
    Dingli, D., Michor, F.: Successful therapy must eradicate cancer stem cells. Stem Cells 24, 2603–2610 (2006)CrossRefGoogle Scholar
  9. 9.
    Dionysiou, D.D., Stamatakos, G.S., Uzunoglu, N.K., Nikita, K.S., Marioli, A.: A fourdimensional simulation model of tumour response to radiotherapy in vivo: parametric validation considering radiosensitivity, genetic profile and fractionation. J. Theor. Biol. 230, 1–20 (2004)CrossRefGoogle Scholar
  10. 10.
    Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J., Schreiber, R.D.: Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002)CrossRefGoogle Scholar
  11. 11.
    Dunn, G.P., Old, L.J., Schreiber, R.D.: The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004)CrossRefGoogle Scholar
  12. 12.
    Enderling, H., Alexander, N.R., Clark, E.S., Branch, K.M., Estrada, L., Crooke, C., Jourquin, J., Lobdell, N., Zaman, M.H., Guelcher, S.A., Anderson, A.R., Weaver, A.M.: Dependence of invadopodia function on collagen fiber spacing and cross-linking: computational modeling and experimental evidence. Biophys. J. 95, 2203–2218 (2008)CrossRefGoogle Scholar
  13. 13.
    Enderling, H., Anderson, A.R., Chaplain, M.A., Beheshti, A., Hlatky, L., Hahnfeldt, P.: Paradoxical dependencies of tumor dormancy and progression on basic cell kinetics. Cancer Res. 69, 8814–8821 (2009)CrossRefGoogle Scholar
  14. 14.
    Enderling, H., Hahnfeldt, P.: Cancer stem cells in solid tumors: Is evading apoptosis a hallmark of cancer? Prog. Biophys. Mol. Biol. 106, 391–399 (2011)CrossRefGoogle Scholar
  15. 15.
    Enderling, H., Hahnfeldt, P., Hlatky, L., Almog, N.: Systems Biology of tumor dormancy: linking biology and mathematics on multiple scales to improve cancer therapy. Cancer Res. 71, 2172–2175 (2012)CrossRefGoogle Scholar
  16. 16.
    Enderling, H., Hlatky, L., Hahnfeldt, P.: Migration rules: tumours are conglomerates of selfmetastases. Br. J. Cancer 100, 1917–1925 (2009)CrossRefGoogle Scholar
  17. 17.
    Enderling, H., Hlatky, L., Hahnfeldt, P.: Tumor morphological evolution: directed migration and gain and loss of the self-metastatic phenotype. Biol. Direct 5, 23 (2010)CrossRefGoogle Scholar
  18. 18.
    Enderling, H., Park, D., Hlatky, L., Hahnfeldt, P.: The importance of spatial distribution of stemness and proliferation state in determining tumor radioresponse. Math. Model. Nat. Phenom. 4, 117–133 (2009)CrossRefMATHGoogle Scholar
  19. 19.
    Folkman, J.: Tumor angiogenesis: therapeutic implications. New Engl. J. Med. 285, 1182–1186 (1971)CrossRefGoogle Scholar
  20. 20.
    Ganguly, R., Puri, I.K.: Mathematical model for the cancer stem cell hypothesis. Cell Prolif. 39, 3–14 (2006)CrossRefGoogle Scholar
  21. 21.
    Gerlee, P., Anderson, A.R.A.: An evolutionary hybrid cellular automaton model of solid tumour growth. J. Theor. Biol. 246, 583–603 (2007)CrossRefGoogle Scholar
  22. 22.
    Glazier, J., Balter, A.:Magnetization to morphogenesis: A brief history of the Glazier-Graner-Hogeweg model. In: Anderson, A.R.A., Chaplain, M.A.J., Rejniak, K.A. (eds) Single-Cell-Based Models in Biology and Medicine. Birkhauser, Basel (2007)Google Scholar
  23. 23.
    Graner, F., Glazier, J.: Simulation of biological cell sorting using a two-dimensional extended Potts model. Phys. Rev. Lett. 69, 2013–2016 (1992)CrossRefGoogle Scholar
  24. 24.
    Hahnfeldt, P., Panigrahy D, Folkman J, Hlatky L.: Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res. 59, 4770–4775 (1999)Google Scholar
  25. 25.
    Hanahan, D., Weinberg, R.A.: The hallmarks of cancer. Cell 100, 57–70 (2000) CrossRefGoogle Scholar
  26. 26.
    Hanahan, D., Weinberg, R.A.: Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)CrossRefGoogle Scholar
  27. 27.
    Hatzikirou, H., Basanta, D., Simon, M., Schaller, K., Deutsch, A.: “Go or Grow”: the key to the emergence of invasion in tumour progression? Math. Med. Biol. 29, 49–65 (2010)CrossRefMATHGoogle Scholar
  28. 28.
    Hegedüs, B., Czirók, A., Fazekas, I., B’abel, T., Madar’asz, E., Vicsek, T.: Locomotion and proliferation of glioblastoma cells in vitro: statistical evaluation of videomicroscopic observations. J. Neurosurg. 92, 428–434 (2000)CrossRefGoogle Scholar
  29. 29.
    Hermann, P.C., Bhaskar, S., Cioffi, M.,Heeschen, C.: Cancer stem cells in solid tumors. Semin. Cancer Biol. 20, 77–84 (2010)CrossRefGoogle Scholar
  30. 30.
    Leder, K., Holland, E.C., Michor, F.: The therapeutic implications of plasticity of the cancer stem cell phenotype. PLoS ONE 5, e14366 (2010)CrossRefGoogle Scholar
  31. 31.
    Marciniak-Czochra, A., Stiehl, T., Ho, A.D., Jaeger,W., Wagner, W.:Modeling of asymmetric cell division in hematopoietic stem cells–regulation of self-renewal is essential for efficient repopulation. Stem Cells Dev. 18 377–385 (2009)CrossRefGoogle Scholar
  32. 32.
    Marian, C.O., Wright, W.E., Shay, J.W.: The effects of telomerase inhibition on prostate tumor-initiating cells. Int. J. Cancer 127, 321–331 (2010)Google Scholar
  33. 33.
    Metropolis, N., Rosenbluth, A.W., Rosenbluth, M.N., Teller, A.H., Teller, E.: Equation of state calculations by fast computing machines. J. Chem. Phys. 21, 1087–1092 (1953) 204 Google Scholar
  34. 34.
    Morton, C.I., Hlatky, L., Hahnfeldt, P., Enderling, H.: Non-stem cancer cell kinetics modulate solid tumor progression. Theor. Biol. Med. Model. 8, 48 (2011)CrossRefGoogle Scholar
  35. 35.
    Mukhopadhyay, R., Costes, S.V., Bazarov, A.V., Hines,W.C., Barcellos-Hoff, M.H., Yaswen, P.: Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies. Breast Cancer Res. 12, R11 (2010)CrossRefGoogle Scholar
  36. 36.
    Nakada, M., Anderson, E.M., Demuth, T., Nakada, S., Reavie, L.B., Drake, K.L., Hoelzinger, D.B., Berens, M.E.: The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. Int. J. Cancer 126 1155–1165 (2010)Google Scholar
  37. 37.
    Norton, L.: Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy. The Oncologist 10, 370–381 (2005)CrossRefGoogle Scholar
  38. 38.
    Norton, L.: Cancer stem cells, self-seeding, and decremented exponential growth: theoretical and clinical implications. Breast Dis. 29, 27–36 (2008)CrossRefGoogle Scholar
  39. 39.
    Piotrowska, M.J., Angus, S.D.: A quantitative cellular automaton model of in vitro multicellular spheroid tumour growth. J. Theor. Biol. 258, 165–178 (2009)CrossRefGoogle Scholar
  40. 40.
    Prehn, R.T.: Immunomodulation of tumor growth. Am. J. Pathol. 77, 119–122 (1974) Google Scholar
  41. 41.
    Prehn, R.T.: The inhibition of tumor growth by tumor mass. Cancer Res. 51, 2–4 (1991)Google Scholar
  42. 42.
    Rejniak, K.A., Anderson, A.R.A.: A computational study of the development of epithelial acini: I. Sufficient conditions for the formation of a hollow structure. Bull. Math. Biol. 70, 677–712 (2008)MATHGoogle Scholar
  43. 43.
    Reya, T., Morrison, S.J., Clarke, M.F., Weissman, I.L.: Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)CrossRefGoogle Scholar
  44. 44.
    Rich, J.N.: Cancer stem cells in radiation resistance. Cancer Res. 67, 8980–8984 (2007) CrossRefGoogle Scholar
  45. 45.
    Sabari, J., Lax, D., Connors, D., Brotman, I., Mindrebo, E., Butler, C., Entersz, I., Jia, D., Foty, R.A.: Fibronectin matrix assembly suppresses dispersal of glioblastoma cells. PLoS ONE 6, e24810 (2011)CrossRefGoogle Scholar
  46. 46.
    Shay, J.W., Wright, W.E.: Telomeres and telomerase in normal and cancer stem cells. FEBS Lett. 584, 3819–3825 (2010)CrossRefGoogle Scholar
  47. 47.
    Solé, R.V., Rodriguez-Caso, C., Deisboeck, T.S., Saldaña, J.: Cancer stem cells as the engine of unstable tumor progression. J. Theor. Biol. 253, 629–637 (2008)CrossRefGoogle Scholar
  48. 48.
    Tang, J., Enderling, H., Becker-Weimann, S., Pham, C., Polyzos, A., Chen, C.Y., Costes, S.V.: Phenotypic transition maps of 3D breast acini obtained by imaging-guided agent-based modeling. Integr. Biol. (Camb) 3, 408–421 (2011)Google Scholar
  49. 49.
    Vermeulen, P.B., van Laere, S.J., Dirix, L.Y.: Inflammatory breast carcinoma as a model of accelerated self-metastatic expansion by intravascular growth. Br. J. Cancer 101, 1028–1029, author reply 1030 (2009)Google Scholar
  50. 50.
    Visvader, J.E., Lindeman, G.J.: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008)CrossRefGoogle Scholar
  51. 51.
    Wang, Z., Zhang, L., Sagotsky, J., Deisboeck, T.S.: Simulating non-small cell lung cancer with a multiscale agent-based model. Theor. Biol. Med. Model. 4, 50 (2007)CrossRefGoogle Scholar
  52. 52.
    Wicha, M.S., Liu, S., Dontu, G.: Cancer stem cells: an old idea–a paradigm shift. Cancer Res. 66, 1883–1890,discussion 1895–1896 (2006)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • Xuefeng Gao
    • 1
  • J. Tyson McDonald
    • 1
  • Lynn Hlatky
    • 1
  • Heiko Enderling
    • 1
  1. 1.Center of Cancer Systems BiologyTufts University School of Medicine, St. Elizabeth’s Medical CenterBostonUSA

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