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Cell Biochemistry and Biophysics

, Volume 63, Issue 3, pp 199–209 | Cite as

Intracellular Mechanics and Activity of Breast Cancer Cells Correlate with Metastatic Potential

  • Naama Gal
  • Daphne WeihsEmail author
Original Paper

Abstract

Mechanics of cancer cells are directly linked to their metastatic potential, or ability to produce a secondary tumor at a distant site. Metastatic cells survive in the circulatory system in a non-adherent state, and can squeeze through barriers in the body. Such considerable structural changes in cells rely on rapid remodeling of internal structure and mechanics. While external mechanical measurements have demonstrated enhanced pliability of cancer cells with increased metastatic potential, little is known about dynamics of their interior and we expect that to change significantly in metastatic cells. We perform a comparative study, using particle-tracking to evaluate the intracellular mechanics of living epithelial breast cells with varying invasiveness. Particles in all examined cell lines exhibit super-diffusion with a scaling exponent of 1.4 at short lag times, likely related to active transport by fluctuating microtubules and their associated molecular motors. Specifics of probe-particle transport differ between the cell types, depending on the cytoskeleton network-structure and interactions with it. Our study shows that the internal microenvironment of the highly metastatic cells evaluated here is more pliable and their cytoskeleton is less dense than the poorly metastatic and benign cells. We thus reveal intracellular structure and mechanics that can support the unique function and invasive capabilities of highly metastatic cells.

Keywords

Particle tracking Cell mechanics Real time imaging in living cells 

Notes

Acknowledgments

The study was partially funded by Israeli Ministry of Science and Technology and by the Technion Russel Berrie Nanotechnology Institute. Confocal imaging was performed at the facilities of the Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering.

Supplementary material

12013_2012_9356_MOESM1_ESM.docx (1.9 mb)
Supplementary material 1 (DOCX 1937 kb)

References

  1. 1.
    Discher, D. E., Janmey, P., & Wang, Y. L. (2005). Tissue cells feel and respond to the stiffness of their substrate. Science, 310, 1139–1143.PubMedCrossRefGoogle Scholar
  2. 2.
    An, S. S., Fabry, B., Trepat, X., Wang, N., & Fredberg, J. J. (2006). Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness? American Journal of Respiratory Cell and Molecular Biology, 35, 55–64.PubMedCrossRefGoogle Scholar
  3. 3.
    Suresh, S., Spatz, J., Mills, J. P., Micoulet, A., Dao, M., Lim, C. T., et al. (2005). Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria. Acta Biomaterialia, 1, 15–30.PubMedCrossRefGoogle Scholar
  4. 4.
    Shaked, N. T., Satterwhite, L. L., Telen, M. J., Truskey, G. A., and Wax, A. (2011). Quantitative microscopy and nanoscopy of sickle red blood cells performed by wide field digital interferometry. Journal of Biomedical Optics 16.Google Scholar
  5. 5.
    Kumar, S., & Weaver, V. (2009). Mechanics, malignancy, and metastasis: The force journey of a tumor cell. Cancer and Metastasis Reviews, 28, 113–127.PubMedCrossRefGoogle Scholar
  6. 6.
    Suresh, S. (2007). Biomechanics and biophysics of cancer cells. Acta Biomaterialia, 3, 413–438.PubMedCrossRefGoogle Scholar
  7. 7.
    Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., et al. (2005). Tensional homeostasis and the malignant phenotype. Cancer Cell, 8, 241–254.PubMedCrossRefGoogle Scholar
  8. 8.
    Janmey, P. A., & Miller, R. T. (2011). Mechanisms of mechanical signaling in development and disease. Journal of Cell Science, 124, 9–18.PubMedCrossRefGoogle Scholar
  9. 9.
    Wirtz, D., Konstantopoulos, K., & Searson, P. C. (2011). The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nature Reviews Cancer, 11, 512–522.PubMedCrossRefGoogle Scholar
  10. 10.
    Guck, J., Schinkinger, S., Lincoln, B., Wottawah, F., Ebert, S., Romeyke, M., et al. (2005). Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophysical Journal, 88, 3689–3698.PubMedCrossRefGoogle Scholar
  11. 11.
    Asnacios, A., Desprat, N., and Guiroy, A. (2006). Microplates-based rheometer for a single living cell. Review of Scientific Instruments 77.Google Scholar
  12. 12.
    Cross, S. E., Jin, Y. S., Rao, J., & Gimzewski, J. K. (2007). Nanomechanical analysis of cells from cancer patients. Nature Nanotechnology, 2, 780–783.PubMedCrossRefGoogle Scholar
  13. 13.
    Fritsch, A., Hockel, M., Kiessling, T., Nnetu, K. D., Wetzel, F., Zink, M., et al. (2010). Are biomechanical changes necessary for tumour progression? Nature Physics, 6, 730–732.CrossRefGoogle Scholar
  14. 14.
    Pelling, A. E., Dawson, D. W., Carreon, D. M., Christiansen, J. J., Shen, R. R., Teitell, M. A., et al. (2007). Distinct contributions of microtubule subtypes to cell membrane shape and stability. Nanomed-Nanotechnol, 3, 43–52.CrossRefGoogle Scholar
  15. 15.
    Weihs, D., Mason, T. G., and Teitell, M. A. (2007). Effects of cytoskeletal disruption on transport, structure, and rheology within mammalian cells. Physics Fluids 19.Google Scholar
  16. 16.
    Weihs, D., Mason, T. G., & Teitell, M. A. (2006). Bio-microrheology: A frontier in microrheology. Biophysical Journal, 91, 4296–4305.PubMedCrossRefGoogle Scholar
  17. 17.
    Hoffman, B. D., & Crocker, J. C. (2009). Cell mechanics: dissecting the physical responses of cells to force. Annual Review of Biomedical Engineering, 11, 259–288.PubMedCrossRefGoogle Scholar
  18. 18.
    Gal, N., and Weihs, D. (2010). Experimental evidence of strong anomalous diffusion in living cells. Physical Review E 81, 020903(R).Google Scholar
  19. 19.
    Arcizet, D., Meier, B., Sackmann, E., Radler, J. O., and Heinrich, D. (2008). Temporal analysis of active and passive transport in living cells. Physical Review Letter 101.Google Scholar
  20. 20.
    Hoffman, B. D., Massiera, G., Van Citters, K. M., & Crocker, J. C. (2006). The consensus mechanics of cultured mammalian cells. Proceedings of National Academy of Sciences USA, 103, 10259–10264.CrossRefGoogle Scholar
  21. 21.
    Caspi, A., Granek, R., & Elbaum, M. (2000). Enhanced diffusion in active intracellular transport. Physical Review Letters, 85, 5655–5658.PubMedCrossRefGoogle Scholar
  22. 22.
    Yamada, S., Wirtz, D., & Kuo, S. C. (2000). Mechanics of living cells measured by laser tracking microrheology. Biophysical Journal, 78, 1736–1747.PubMedCrossRefGoogle Scholar
  23. 23.
    Kulkarni, R. P., Castelino, K., Majumdar, A., & Fraser, S. E. (2006). Intracellular transport dynamics of endosomes containing DNA polyplexes along the microtubule network. Biophysical Journal, 90, L42–L44.PubMedCrossRefGoogle Scholar
  24. 24.
    Robert, D., Nguyen, T. H., Gallet, F., and Wilhelm, C. (2010). In vivo determination of fluctuating forces during endosome trafficking using a combination of active and passive microrheology. PLoS ONE 5.Google Scholar
  25. 25.
    Li, Y. X., Schnekenburger, J., and Duits, M. H. G. (2009). Intracellular particle tracking as a tool for tumor cell characterization. Journal of Biomedical Optics 14.Google Scholar
  26. 26.
    Yizraeli, M. L., and Weihs, D. (2011). Time-dependent micromechanical responses of breast cancer cells and adjacent fibroblasts to electric treatment. Cell Biochemistry and Biophysics (in press).Google Scholar
  27. 27.
    Crocker, J. C., & Grier, D. G. (1996). Methods of digital video microscopy for colloidal studies. Journal of Colloid and Interface Science, 179, 298–310.CrossRefGoogle Scholar
  28. 28.
    Brangwynne, C. P., Koenderink, G. H., Weitz, D. A., & MacKintosh, F. C. (2009). Intracellular transport by active diffusion. Trends in Cell Biology, 19, 423–427.PubMedCrossRefGoogle Scholar
  29. 29.
    Saxton, M. J., & Jacobson, K. (1997). Single-particle tracking: Applications to membrane dynamics. Annual Review of Biophysics and Biomolecular Structure, 26, 373–399.PubMedCrossRefGoogle Scholar
  30. 30.
    Metzler, R., & Klafter, J. (2000). The random walk’s guide to anomalous diffusion: a fractional dynamics approach. Physics Reports, 339, 1–77.CrossRefGoogle Scholar
  31. 31.
    Burov, S., Jeon, J. H., Metzler, R., & Barkai, E. (2011). Single particle tracking in systems showing anomalous diffusion: the role of weak ergodicity breaking. Physical Chemistry Chemical Physics: PCCP, 13, 1800–1812.PubMedCrossRefGoogle Scholar
  32. 32.
    Brangwynne, C. P., Koenderink, G. H., MacKintosh, F. C., and Weitz, D. A. (2008). Nonequilibrium microtubule fluctuations in a model cytoskeleton. Physical Review Letter 100.Google Scholar
  33. 33.
    Savin, T., & Doyle, P. S. (2005). Static and dynamic errors in particle tracking microrheology. Biophysical Journal, 88, 623–638.PubMedCrossRefGoogle Scholar
  34. 34.
    Castiglione, P., Mazzino, A., Muratore-Ginanneschi, P., & Vulpiani, A. (1999). On strong anomalous diffusion. Physica D: Nonlinear Phenomena, 134, 75–93.CrossRefGoogle Scholar
  35. 35.
    Ferrari, R., Manfroi, A. J., & Young, W. R. (2001). Strongly and weakly self-similar diffusion. Physica D: Nonlinear Phenomena, 154, 111–137.CrossRefGoogle Scholar
  36. 36.
    Oppong, F. K., & de Bruyn, J. R. (2007). Diffusion of microscopic tracer particles in a yield-stress fluid. J Non-Newton Fluid, 142, 104–111.CrossRefGoogle Scholar
  37. 37.
    Girard, K. D., Kuo, S. C., & Robinson, D. N. (2006). Dictyostelium myosin II mechanochemistry promotes active behavior of the cortex on long time scales. Proceedings of National Academy of Sciences USA, 103, 2103–2108.CrossRefGoogle Scholar
  38. 38.
    Raupach, C., Zitterbart, D. P., Mierke, C. T., Metzner, C., Muller, F. A., and Fabry, B. (2007). Stress fluctuations and motion of cytoskeletal-bound markers. Physical Review E 76.Google Scholar
  39. 39.
    Bronstein, I., Israel, Y., Kepten, E., Mai, S., Shav-Tal, Y., Barkai, E., and Garini, Y. (2009). Transient anomalous diffusion of telomeres in the nucleus of mammalian cells. Physical Review Letter 103.Google Scholar
  40. 40.
    Caspi, A., Granek, R., and Elbaum, M. (2002). Diffusion and directed motion in cellular transport. Physical Review E Statistical, Nonlinear, and Soft Matter Physics 66, 011916.Google Scholar
  41. 41.
    Snider, J., Lin, F., Zahedi, N., Rodionov, V., Yu, C. C., & Gross, S. P. (2004). Intracellular actin-based transport: How far you go depends on how often you switch. Proceedings of National Academy of Sciences USA, 101, 13204–13209.CrossRefGoogle Scholar
  42. 42.
    Umansky, M., and Weihs, D. (2012). Novel algorithm and MATLAB-based program for automated power law analysis of single particle. Time-dependent mean-square displacement. Computer Physics Communications (in press).Google Scholar
  43. 43.
    Lau, A. W. C., Hoffman, B. D., Davies, A., Crocker, J. C., and Lubensky, T. C. (2003). Microrheology, stress fluctuations, and active behavior of living cells. Physical Review Letter 91.Google Scholar
  44. 44.
    Wilhelm, C. (2008). Out-of-equilibrium microrheology inside living cells. Physical Review Letter 101. Google Scholar
  45. 45.
    Kulic, I. M., Brown, A. E., Kim, H., Kural, C., Blehm, B., Selvin, P. R., et al. (2008). The role of microtubule movement in bidirectional organelle transport. Proceedings of National Academy of Sciences USA, 105, 10011–10016.CrossRefGoogle Scholar
  46. 46.
    Li, Q. S., Lee, G. Y. H., Ong, C. N., & Lim, C. T. (2008). AFM indentation study of breast cancer cells. Biochemical and Biophysical Research Communications, 374, 609–613.PubMedCrossRefGoogle Scholar
  47. 47.
    Mizuno, D., Tardin, C., Schmidt, C. F., & MacKintosh, F. C. (2007). Nonequilibrium mechanics of active cytoskeletal networks. Science, 315, 370–373.PubMedCrossRefGoogle Scholar
  48. 48.
    Bursac, P., Lenormand, G., Fabry, B., Oliver, M., Weitz, D. A., Viasnoff, V., et al. (2005). Cytoskeletal remodelling and slow dynamics in the living cell. Nature Materials, 4, 557–561.PubMedCrossRefGoogle Scholar
  49. 49.
    Lin, Y. C., Koenderink, G. H., MacKintosh, F. C., & Weitz, D. A. (2007). Viscoelastic properties of microtubule networks. Macromolecules, 40, 7714–7720.CrossRefGoogle Scholar
  50. 50.
    Pelletier, V., Gal, N., Fournier, P., and Kilfoil, M. L. (2009). Microrheology of Microtubule Solutions and actin-microtubule composite networks. Physical Review Letter 102.Google Scholar
  51. 51.
    Caspi, A., Granek, R., Lachish, A., Zbaida, D., & Elbaum, M. (1998). Semiflexible polymer network: A view from inside. Physical Review Letters, 80, 1106–1109.CrossRefGoogle Scholar
  52. 52.
    Kural, C., Kim, H., Syed, S., Goshima, G., Gelfand, V. I., & Selvin, P. R. (2005). Kinesin and dynein move a peroxisome in vivo: A tug-of-war or coordinated movement? Science, 308, 1469–1472.PubMedCrossRefGoogle Scholar
  53. 53.
    Lipowsky, R., Klumpp, S., & Nieuwenhuizen, T. M. (2001). Random walks of cytoskeletal motors in open and closed compartments. Physical Review Letters, 87, 108101.PubMedCrossRefGoogle Scholar
  54. 54.
    Kahana, A., Kenan, G., Feingold, M., Elbaum, M., and Granek, R. (2008). Active transport on disordered microtubule networks: The generalized random velocity model. Physical Review E Statistical Nonlinear Soft Matter Physics 78, 051912.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Technion-Israel Institute of TechnologyHaifaIsrael

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