Abstract
Defining the characteristics of cancer stem cells (CSC) has become an important subject in cancer research during the past decade. Although molecular surface expression levels have been used for CSC recognition, the clinical and prognostic impacts of these markers have remained a controversial issue. The finding that cancerous cells are considerably more deformable than normal ones provides the motivation for the hypothesis that the mechanical properties can be used as biomarkers to distinguish between stem-like and non-stem-like cancer cells. In this study, using micropipette aspiration (MA) and intracellular particle tracking (IPT) microrheology, measurements of the whole-cell and local viscoelasticity were made on four breast cancer cell lines with different CSC phenotypes based on their surface markers. Stem-like Hs578T and MDA-MB-231 cell lines were found to be the most deformable, while the non-stem-like MDA-MB-468 line was the least deformable. The non-stem-like BT-20 cell line showed an intermediate deformability. The enhanced deformability for stem-like cells was consistent with the observed lower and more dispersed F-actin content for the stem-like cells. Therefore, the cytoskeleton-related differences in the rheological properties of cancer cells can be a potential biomarker for CSC and eventually lead to novel cancer diagnostic and therapeutic methods.
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Al-Hajj, M., M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F. Clarke. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. 100:3983–3988, 2003.
Boal, D. Three-Dimensional Networks in Mechanics of the Cell. New York: Cambridge University Press, pp. 97–131, 2002.
Burdick, M. M., K. A. Henson, L. F. Delgadillo, Y. E. Choi, D. J. Goetz, D. F. J. Tees, and F. Benencia. Expression of E-selectin ligands on circulating tumor cells: cross-regulation with cancer stem cell regulatory pathways? Front. Oncol. 2(103):1–11, 2012.
Caspi, A., R. Granek, and M. Elbaum. Enhanced diffusion in active intracellular transport. Phys. Rev. Lett. 85:5655–5658, 2000.
Crocker, J. C., and B. D. Hoffman. Multiple-particle tracking and two-point microrheology in cells. Methods Cell Biol. 83:141–178, 2007.
Curran-Everett, D. Multiple comparisons: philosophies and illustrations. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279:R1–R8, 2000.
Duits, M. H. G., Y. Li, S. A. Vanapalli, and F. Mugele. Mapping of spatiotemporal heterogeneous particle dynamics in living cells. Phys. Rev. E 79:1–11, 2009.
Egeblad, M., S. N. Nakason, and Z. Werb. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18(6):884–901, 2010.
Guck, J., S. Schinkinger, B. Lincoln, F. Wottawah, S. Ebert, M. Romeyke, D. Lenz, H. M. Erickson, R. Ananthakrishnan, D. Mitchell, J. Kas, S. Ulvick, and C. Bilby. Optical deformability as an Inherent Cell marker for testing malignant transformation and metastatic competence. Biophys. J. 88:3689–3698, 2005.
Hanahan, D., and R. A. Weinberg. Hallmarks of cancer: the next generation. Cell 144:646–674, 2011.
Hoffman, B. D., and J. C. Crocker. Cell mechanics: dissecting the physical responses of cells to force. Ann. Rev. Biomed. Eng. 11:259–288, 2009.
Hoffman, B. D., G. Massiera, K. M. Van Citters, and J. C. Crocker. The consensus mechanics of cultured mammalian cells. Proc. Natl. Acad. Sci. USA 103:10259–10264, 2006.
Jacobs, C. R., H. Huang, and R. Y. Kwon. Introduction to cell mechanics and mechanobiology. Garland Sci. 19:151–153, 2012.
Kim, Y., K. M. Joo, J. Jin, and D. Nam. Cancer stem cells and their mechanism of chemo-radiation resistance. Int. J. Stem Cells 2(2):109–114, 2009.
Kojić, N., M. Milošević, D. Petrović, V. Isailović, A. F. Sarioglu, D. A. Haber, M. Kojić, and M. A. Toner. Computational study of circulating large tumor cells traversing microvessels. Comput. Biol. Med. 63:187–195, 2015.
Lammerding, J., K. N. Dahl, D. E. Discher, and R. D. Kamm. Methods in cell biology. Nucl. Mech. Methods 83:269–294, 2007.
Lee, G. Y. H., and C. T. Lim. Biomechanics approaches to studying human diseases. Trends Biotechnol. 25:111–118, 2007.
Lekka, M., P. Laidler, D. Gil, J. Lekki, Z. Stachura, and A. Z. Hrynkiewicz. Elasticity of normal and cancerous human bladder cells studied by scanning force microscopy Eur. Biophys. J. 28:312–316, 1999.
Li, Y., J. Schnekenburger, and M. H. G. Duits. Intracellular particle tracking as a tool for tumor cell characterization. J. Biomed. Opt. 14(6):1–7, 2009.
Lim, C. T., E. Z. Zhou, and S. T. Quek. Mechanical models for living cells– a review. J. Biomech. 39:195–216, 2006.
Lincoln, B., H. M. Erickson, S. Schinkinger, F. Wottawah, D. Mitchell, S. Ulvick, C. Bilby, and J. Guck. Deformability-based flow cytometry. Cytom. A 59(2):203–209, 2004.
Louie, E., S. Nik, J. Chen, M. Schmidt, B. Song, C. Pacson, X. F. Chen, S. Park, J. Ju, and E. Chen. Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res. 12(6):R94, 2010.
Mason, T. G., and K. Ganesan. Particle tracking microrheology of complex fluids. Phys. Rev. Lett. 79:3282–3285, 1997.
Merryman, W. D., P. D. Bieniek, F. Guilak, and M. S. Sacks. Viscoelastic properties of the aortic valve interstitial cell. J. Biomech. Eng. 131(4):041005, 2009.
Pai, A., P. Sundd, and D. F. J. Tees. In situ microrheological determination of neutrophil stiffening following adhesion in a model capillary. Ann. Biomed. Eng. 36:596–603, 2008.
Pangarkar, C., A. T. Dinh, and S. Mitragotri. Dynamics and spatial organization of endosomes in mammalian cells. Phys. Rev. Lett. 95:158101, 2005.
Petrie, R. J., H. Koo, and K. M. Yamada. Generation of compartmentalized pressure by a nuclear piston governs cell motility in 3D matrix. Science 345(6200):1062–1065, 2014.
Prise, K. M., and A. Saran. Concise review: stem cell effects in radiation risk. Stem Cells 29:1315–1321, 2011.
Sato, M., D. P. Theret, L. T. Wheeler, N. Ohshima, and R. M. Nerem. Application of the micropipette technique to the measurement of cultured porcine aortic endothelial cell viscoelastic properties. J. Biomech. Eng. 112:263–268, 1990.
Schmid-Schonbein, G. W., K. L. Sung, H. Tozeren, R. Skalak, and S. Chien. Passive mechanical properties of human leukocytes. Biophys. J. 36:243–256, 1981.
Sehl, M. E., M. Shimada, A. Landeros, K. Lange, and M. S. Wicha. Modeling of cancer stem cell state transitions predicts therapeutic response. PLoS ONE 10(9):e0135797, 2015.
Sheridan, C., H. Kishimoto, R. K. Fuchs, S. Mehrotra, P. Bhat-Nakshatri, C. H. Turner, and R. Jr. Goulet, S. Badve, and H. Nakshatri. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 8(5):R59, 2006.
Snider, J., F. Lin, N. Zahedi, V. Rodionov, C. C. Yu, and S. P. Gross. Intracellular actin-based transport: how far you go depends on how often you switch. Proc. Natl. Acad. Sci. USA 101:13204–13209, 2004.
Stroka, K. M., Z. Gu, S. X. Sun, and K. Konstantopoulos. Bioengineering paradigms for cell migration in confined microenvironments. Curr. Opin. Cell Biol. 30:42–50, 2014.
Stroka, K. M., H. Jiang, S. Chen, Z. Tong, D. Wirtz, S. X. Sun, and K. Konstantopoulos. Water permeation drives tumor cell migration in confined microenvironments. Cell 157:611–623, 2014.
Sundd, P., X. Zou, D. J. Goetz, and D. F. J. Tees. Leukocyte adhesion in capillary-sized, P selectin-coated micropipettes. Microcirculation 15:109–122, 2008.
Tees, D. F. J., R. E. Waugh, and D. A. Hammer. A microcantilever device to assess the effect of force on the lifetime of selectin-carbohydrate bonds. Biophys. J. 80:668–682, 2001.
Thiery, J. P., and J. P. Sleeman. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7:131–142, 2006.
Tseng, Y., T. P. Kole, and D. Wirtz. Micromechanical mapping of live cells by multiple-particle-tracking microrheology. Biophys. J. 83:3162–3176, 2002.
Wirtz, D., K. Konstantopoulos, and P. C. Searson. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat. Rev. Cancer 11:512–522, 2011.
Wu, Z. Z., G. Zhang, M. Long, H. B. Wang, G. B. Song, and S. X. Cai. Comparison of the viscoelastic properties of normal hepatocytes and hepatocellular carcinoma cells under cytoskeletal perturbation. Biorheology 37:279–290, 2000.
Wyckoff, J. B., J. G. Jones, J. S. Condeelis, and J. E. Segall. A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res. 60:2504–2511, 2000.
Yanai, M., J. P. Butler, T. Suzuki, A. Kanda, M. Kurachi, H. Tashiro, and H. Sasaki. Intracellular elasticity and viscosity in the body, leading, and trailing regions of locomoting neutrophils. Am. J. Physiol. Cell Physiol. 277:C432–C440, 1999.
Yanai, M., J. P. Butler, T. Suzuki, H. Sasaki, and H. Higuchi. Regional rheological differences in locomoting neutrophils. Am. J. Physiol. Cell Physiol. 287:C603–C611, 2004.
Yap, B., and R. D. Kamm. Mechanical deformation of neutrophils into narrow channels induces pseudopod projection and changes in biomechanical properties. J. Appl. Physiol. 98:1930–1939, 2005.
Zhou, E. H., S. T. Quek, and C. T. Lim. Power-law rheology analysis of cells undergoing micropipette aspiration. Biomech. Model. Mechanobiol. 9:563–572, 2010.
Acknowledgments
This work was supported by National Science Foundation grants CBET-1106118 and Major Research Instrumentation CBET-1039869. The authors would like to thank Mr. Grady Carlson (Department of Chemical and Biomolecular Engineering, Ohio University) for his collaboration and help in lab instruction.
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Amina Mohammadalipour, Monica Burdick and David Tees declare that they have no conflict of interest.
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Mohammadalipour, A., Burdick, M.M. & Tees, D.F.J. Viscoelasticity Measurements Reveal Rheological Differences Between Stem-like and Non-stem-like Breast Cancer Cells. Cel. Mol. Bioeng. 10, 235–248 (2017). https://doi.org/10.1007/s12195-017-0485-8
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DOI: https://doi.org/10.1007/s12195-017-0485-8