Cellular and Molecular Bioengineering

, Volume 9, Issue 3, pp 398–417 | Cite as

Mechanical Properties of the Tumor Stromal Microenvironment Probed In Vitro and Ex Vivo by In Situ-Calibrated Optical Trap-Based Active Microrheology

  • Jack R. Staunton
  • Wilfred Vieira
  • King Leung Fung
  • Ross Lake
  • Alexus Devine
  • Kandice Tanner


One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue’s mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs. Here we investigate the effects of intrinsic spatial heterogeneities due to fibrillar architecture, pore size and ligand density on the microscale and bulk mechanical properties of the ECM. Type I collagen hydrogels with topologies tuned by polymerization temperature and concentration to mimic physico-chemical properties of a normal tissue and tumor microenvironment were measured by in situ-calibrated Active Microrheology by Optical Trapping revealing significantly different microscale complex shear moduli at Hz-kHz frequencies and two orders of magnitude of strain amplitude that we compared to data from bulk rheology measurements. Access to higher frequencies enabled observation of transitions from elastic to viscous behavior that occur at ~200–2750 Hz, which largely was dependent on tissue architecture well outside the dynamic range of instrument acquisition possible with SAOS bulk rheology. We determined that mouse melanoma tumors and human breast tumors displayed complex moduli ~5–1000 Pa, increasing with frequency and displaying a nonlinear stress–strain response. Thus, we show the feasibility of a mechanical biopsy in efforts to provide a diagnostic tool to aid in the design of therapeutics complementary to those based on standard histopathology.


Microrheology Optical traps Biomaterials Tissue mechanics Hydrogels Biopsy 



This effort was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. We thank Ben Blehm for helpful technical discussions and George Leiman for critical reading of the manuscript. We also thank Daniel Blair, and Xinran Zhang of Georgetown University for assistance with bulk rheometry.

Conflict of interest

Dr. Tanner and Alexus Devine have an international stage PCT application pending. Jack R Staunton, Wilfred Vieira, King Leung Fung and Ross Lake, all declare that they have no conflict of interest.

Ethical Statements

Animal studies were conducted under protocols approved by the National Cancer Institute, and the National Institutes of Health Animal Care and Use Committee. No human subjects research was performed in this studies.

Supplementary material

12195_2016_460_MOESM1_ESM.docx (375 kb)
Supplementary material 1 (DOCX 374 kb)


  1. 1.
    Abidine, Y., R. Michel, A. Duperray, L. Iulian, C. Verdier, Y. Abidine, et al. Physical properties of polyacrylamide gels probed by AFM and rheology. EPL Eur. Phys. Soc. 109:38003, 2015.Google Scholar
  2. 2.
    Acerbi, I., L. Cassereau, I. Dean, Q. Shi, A. Au, C. Park, et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7(10):1120–1134, 2015. doi: 10.1039/c5ib00040h.CrossRefGoogle Scholar
  3. 3.
    Alcaraz, J., L. Buscemi, M. Grabulosa, X. Trepat, B. Fabry, R. Farré, and D. Navajas. Microrheology of human lung epithelial cells measured by atomic force microscopy. Biophys. J. 84(3):2071–2079, 2003. doi: 10.1016/S0006-3495(03)75014-0.CrossRefGoogle Scholar
  4. 4.
    Alexander, S., B. Weigelin, F. Winkler, and P. Friedl. Preclinical intravital microscopy of the tumour-stroma interface: invasion, metastasis, and therapy response. Curr. Opin. Cell Biol. 25(5):659–671, 2013. doi: 10.1016/j.ceb.2013.07.001.CrossRefGoogle Scholar
  5. 5.
    An, K. N., Y. L. Sun, and Z. P. Luo. Flexibility of type I collagen and mechanical property of connective tissue. Biorheology 41(3–4):239–246, 2004.Google Scholar
  6. 6.
    Arevalo, R. C., J. S. Urbach, and D. L. Blair. Size-dependent rheology of type-I collagen networks. Biophys. J. 99(8):L65–L67, 2010. doi: 10.1016/j.bpj.2010.08.008.CrossRefGoogle Scholar
  7. 7.
    Barcus, C. E., P. J. Keely, K. W. Eliceiri, and L. A. Schuler. Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J. Biol. Chem. 288(18):12722–12732, 2013. doi: 10.1074/jbc.M112.447631.CrossRefGoogle Scholar
  8. 8.
    Berg-sørensen, K., and H. Flyvbjerg. Power spectrum analysis for optical tweezers Power spectrum analysis for optical tweezers. Rev. Sci. Instrum. 594(75):594, 2004. doi: 10.1063/1.1645654.CrossRefGoogle Scholar
  9. 9.
    Blehm, B. H., A. Devine, J. R. Staunton, and K. Tanner. In vivo tissue has non-linear rheological behavior distinct from 3D biomimetic hydrogels as determined by AMOTIV microscopy. Biomaterials 83:66–78, 2015. doi: 10.1016/j.biomaterials.2015.12.019.CrossRefGoogle Scholar
  10. 10.
    Blehm, B. H., T. A. Schroer, K. M. Trybus, Y. R. Chemla, P. R. Selvin, B. H. Blehm, et al. In vivo optical trapping indicates kinesin’s stall force is reduced by dynein during intracellular transport. Proc. Natl. Acad. Sci. 110(23):1–7, 2013. doi: 10.1073/pnas.1308350110.Google Scholar
  11. 11.
    Brau, R. R., J. M. Ferrer, H. Lee, C. E. Castro, and B. K. Tam. Passive and active microrheology with optical tweezers. J. Opt. A: Pure Appl. Opt. 9:S103–S112, 2007. doi: 10.1088/1464-4258/9/8/S01.CrossRefGoogle Scholar
  12. 12.
    Bredfeldt, J. S., Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri. Automated quantification of aligned collagen for human breast carcinoma prognosis. J. Pathol. Inf. 5:28, 2014. doi: 10.4103/2153-3539.139707.CrossRefGoogle Scholar
  13. 13.
    Bredfeldt, J. S., Y. Liu, C. A. Pehlke, M. W. Conklin, J. M. Szulczewski, D. R. Inman, et al. Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer. J. Biomed. Opt. 19(1):16007, 2014. doi: 10.1117/1.JBO.19.1.016007.CrossRefGoogle Scholar
  14. 14.
    Breedveld, V., and D. J. Pine. Microrheology as a tool for high-throughput screening. J. Mater. Sci. 38(22):4461–4470, 2003. doi: 10.1023/A:1027321232318.CrossRefGoogle Scholar
  15. 15.
    Brábek, J., C. T. Mierke, D. Rösel, P. Veselý, and B. Fabry. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion. Cell Commun. Signal. CCS 8:22, 2010. doi: 10.1186/1478-811X-8-22.CrossRefGoogle Scholar
  16. 16.
    Carlisle, C. R., C. Coulais, and M. Guthold. The mechanical stress-strain properties of single electrospun collagen type I nanofibers. Acta Biomater. 6(8):2997–3003, 2010. doi: 10.1016/j.actbio.2010.02.050.CrossRefGoogle Scholar
  17. 17.
    Conklin, M. W., J. C. Eickhoff, K. M. Riching, C. A. Pehlke, K. W. Eliceiri, P. P. Provenzano, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178(3):1221–1232, 2011. doi: 10.1016/j.ajpath.2010.11.076.CrossRefGoogle Scholar
  18. 18.
    Cox, G., E. Kable, A. Jones, I. Fraser, F. Manconi, and M. D. Gorrell. 3-Dimensional imaging of collagen using second harmonic generation. J. Struct. Biol. 141(1):53–62, 2003. doi: 10.1016/S1047-8477(02)00576-2.CrossRefGoogle Scholar
  19. 19.
    Cukierman, E., R. Pankov, and K. M. Yamada. Cell interactions with three-dimensional matrices. Curr. Opin. Cell Biol. 14(5):633–639, 2002.CrossRefGoogle Scholar
  20. 20.
    De Wever, O., and M. Mareel. Role of tissue stroma in cancer cell invasion. J. Pathol. 200(4):429–447, 2003. doi: 10.1002/path.1398.CrossRefGoogle Scholar
  21. 21.
    Deffieux, T., G. Montaldo, M. Tanter, and M. Fink. Shear wave spectroscopy for in vivo quantification of human soft tissues visco-elasticity. IEEE Trans. Med. Imaging 28(3):313–322, 2009. doi: 10.1109/TMI.2008.925077.CrossRefGoogle Scholar
  22. 22.
    Doyle, A. D., N. Carvajal, A. Jin, K. Matsumoto, and K. M. Yamada. Local 3D matrix microenvironment regulates cell migration through spatiotemporal dynamics of contractility-dependent adhesions. Nat. Commun. 6:8720, 2015. doi: 10.1038/ncomms9720.CrossRefGoogle Scholar
  23. 23.
    Doyle, A. D., F. W. Wang, K. Matsumoto, and K. M. Yamada. One-dimensional topography underlies three-dimensional fibrillar cell migration. J. Cell Biol. 184(4):481–490, 2009. doi: 10.1083/jcb.200810041.CrossRefGoogle Scholar
  24. 24.
    Egeblad, M., M. G. Rasch, and V. M. Weaver. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 22(5):697–706, 2010. doi: 10.1016/j.ceb.2010.08.015.CrossRefGoogle Scholar
  25. 25.
    Entenberg, D., Kedrin, D., Wyckoff, J., Sahai, E., Condeelis, J., & Segall, J. E. (2013). Imaging tumor cell movement in vivo. Curr. Protoc. Cell Biol. Chapter 19, Unit19.7.  10.1002/0471143030.cb1907s58.
  26. 26.
    Ewoldt, R. H., A. E. Hosoi, and G. H. Mckinley. New measures for characterizing nonlinear viscoelasticity in large amplitude oscillatory shear (LAOS). J. Rheol. 52:1427, 2008.CrossRefGoogle Scholar
  27. 27.
    Ewoldt, R. H., P. Winter, J. Maxey, and G. H. Mckinley. Large amplitude oscillatory shear of pseudoplastic and elastoviscoplastic materials. Rheol. Acta 49:191–212, 2010.CrossRefGoogle Scholar
  28. 28.
    Fabry, B., G. Maksym, J. Butler, M. Glogauer, D. Navajas, N. Taback, et al. Time scale and other invariants of integrative mechanical behavior in living cells. Phys. Rev. E 68(4):1–18, 2003. doi: 10.1103/PhysRevE.68.041914.CrossRefGoogle Scholar
  29. 29.
    Farré, A., and M. Montes-usategui. A force detection technique for single-beam optical traps based on direct measurement of light momentum changes. Opt. Exp. 18(11):2382–2391, 2010.CrossRefGoogle Scholar
  30. 30.
    Fidler, I. J. The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nat. Rev. Cancer 3(6):453–458, 2003. doi: 10.1038/nrc1098.CrossRefGoogle Scholar
  31. 31.
    Fischer, M., and K. Berg-sørensen. Calibration of trapping force and response function of optical tweezers in viscoelastic media. J. Opt. A 9(8): S239. Retrieved from http://stacks.iop.org/1464-4258/9/i=8/a=S18, 2007
  32. 32.
    Fraley, S. I., P. Wu, L. He, Y. Feng, R. Krisnamurthy, G. D. Longmore, and D. Wirtz. Three-dimensional matrix fiber alignment modulates cell migration and MT1-MMP utility by spatially and temporally directing protrusions. Sci. Rep. 5:14580, 2015.CrossRefGoogle Scholar
  33. 33.
    Fratzl, P., K. Misof, I. Zizak, G. Rapp, H. Amenitsch, and S. Bernstorff. Fibrillar structure and mechanical properties of collagen. J. Struct. Biol. 122(1–2):119–122, 1998. doi: 10.1006/jsbi.1998.3966.CrossRefGoogle Scholar
  34. 34.
    Friedl, P., and S. Alexander. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147(5):992–1009, 2011. doi: 10.1016/j.cell.2011.11.016.CrossRefGoogle Scholar
  35. 35.
    Friedl, P., and K. Wolf. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3(May):362–374, 2003. doi: 10.1038/nrc1075.CrossRefGoogle Scholar
  36. 36.
    Friedl, P., and K. Wolf. Proteolytic interstitial cell migration: a five-step process. Cancer Metastasis Rev. 28(1–2):129–135, 2009. doi: 10.1007/s10555-008-9174-3.CrossRefGoogle Scholar
  37. 37.
    Gentleman, E., A. N. Lay, D. A. Dickerson, E. A. Nauman, G. A. Livesay, and K. C. Dee. Mechanical characterization of collagen fibers and scaffolds for tissue engineering. Biomaterials 24(21):3805–3813, 2003. doi: 10.1016/S0142-9612(03)00206-0.CrossRefGoogle Scholar
  38. 38.
    Gilkes, D. M., P. Chaturvedi, S. Bajpai, C. C. Wong, H. Wei, S. Pitcairn, et al. Collagen prolyl hydroxylases are essential for breast cancer metastasis. Cancer Res. 73(11):3285–3296, 2013. doi: 10.1158/0008-5472.CAN-12-3963.CrossRefGoogle Scholar
  39. 39.
    Gittes, F., and C. F. Schmidt. Interference model for back-focal-plane displacement detection in optical tweezers. Opt. Lett. 23(1):7–9, 1998.CrossRefGoogle Scholar
  40. 40.
    Granek, R., and M. E. Cates. Stress relaxation in living polymers: results from a Poisson renewal model. J. Chem. Phys. 96:4758, 1992. doi: 10.1063/1.462787.CrossRefGoogle Scholar
  41. 41.
    Grange, W., S. Husale, H. Güntherodt, and M. Hegner. Optical tweezers system measuring the change in light momentum flux. Rev. Sci. Instrum. 73(6):2308, 2002. doi: 10.1063/1.1477608.CrossRefGoogle Scholar
  42. 42.
    Guthold, M., W. Liu, E. A. Sparks, L. M. Jawerth, L. Peng, M. Falvo, et al. A comparison of the mechanical and structural properties of fibrin fibers with other protein fibers. Cell Biochem. Biophys. 49(3):165–181, 2007. doi: 10.1007/s12013-007-9001-4.CrossRefGoogle Scholar
  43. 43.
    Gutsmann, T., G. E. Fantner, J. H. Kindt, M. Venturoni, S. Danielsen, and P. K. Hansma. Force spectroscopy of collagen fibers to investigate their mechanical properties and structural organization. Biophys. J. 86(5):3186–3193, 2004. doi: 10.1016/S0006-3495(04)74366-0.CrossRefGoogle Scholar
  44. 44.
    Jawerth, L. M., S. Munster, D. A. Vader, B. Fabry, and D. A. Weitz. A blind spot in confocal reflection microscopy: the dependence of fiber brightness on fiber orientation in imaging biopolymer networks. Biophys. J. 98(3):3–5, 2010. doi: 10.1016/j.bpj.2009.09.065.Google Scholar
  45. 45.
    Jun, Y., S. K. Tripathy, B. R. J. Narayanareddy, M. K. Mattson-hoss, and S. P. Gross. Article calibration of optical tweezers for in vivo force measurements: how do different approaches compare? Biophys. J. 107(6):1474–1484, 2014. doi: 10.1016/j.bpj.2014.07.033.CrossRefGoogle Scholar
  46. 46.
    Kadler, K. E., D. F. Holmes, J. A. Trotter, and J. A. Chapman. Collagen fibril formation. J. Biochem. 316(Pt 1):1–11, 1996.CrossRefGoogle Scholar
  47. 47.
    Kalluri, R., and M. Zeisberg. Fibroblasts in cancer. Nat. Rev. Cancer 6(5):392–401, 2006. doi: 10.1038/nrc1877.CrossRefGoogle Scholar
  48. 48.
    Kamm, R. D., and M. R. Mofrad. In: Cytoskeletal Mechanics: Models and Measurements1st, edited by R. D. Kamm, and M. R. Mofrad. New York: Cambridge University Press, 2006.Google Scholar
  49. 49.
    Kasza, K. E., A. C. Rowat, J. Liu, T. E. Angelini, C. P. Brangwynne, G. H. Koenderink, and D. A. Weitz. The cell as a material. Curr. Opin. Cell Biol. 19(1):101–107, 2007. doi: 10.1016/j.ceb.2006.12.002.CrossRefGoogle Scholar
  50. 50.
    Keely, P. J. Mechanisms by which the extracellular matrix and integrin signaling act to regulate the switch between tumor suppression and tumor promotion. J Mammary Gland Biol Neoplasia 16(3):205–219, 2011. doi: 10.1007/s10911-011-9226-0.CrossRefGoogle Scholar
  51. 51.
    Khanna, C., R. G. Wells, E. Puré, and S. W. Volk. Type III collagen directs stromal organization and limits metastasis in a murine model of breast cancer. Am. J. Pathol. 185(5):1, 2015.CrossRefGoogle Scholar
  52. 52.
    Kim, J., J. R. Staunton, and K. Tanner. Independent control of topography for 3D patterning of the ECM microenvironment. Adv. Mater. 28:132–137, 2015. doi: 10.1002/adma.201503950.CrossRefGoogle Scholar
  53. 53.
    Kolahi, K. S., and M. R. K. Mofrad. Mechanotransduction: a major regulator of homeostasis and development. Wiley Interdiscip. Rev. 2(6):625–639, 2010. doi: 10.1002/wsbm.79.Google Scholar
  54. 54.
    Kotlarchyk, M. A., E. L. Botvinick, and A. J. Putnam. Characterization of hydrogel microstructure using laser tweezers particle tracking and confocal reflection imaging. J. Phys.: Condens. Matter 22(19):194121, 2010. doi: 10.1088/0953-8984/22/19/194121.Google Scholar
  55. 55.
    Kotlarchyk, M. A., S. G. Shreim, M. B. Alvarez-Elizondo, L. C. Estrada, R. Singh, L. Valdevit, et al. Concentration independent modulation of local micromechanics in a fibrin gel. PLoS One 6(5):e20201, 2011. doi: 10.1371/journal.pone.0020201.CrossRefGoogle Scholar
  56. 56.
    Leight, J. L., M. A. Wozniak, S. Chen, M. L. Lynch, and C. S. Chen. Matrix rigidity regulates a switch between TGF-1-induced apoptosis and epithelial-mesenchymal transition. Mol. Biol. Cell 23(5):781–791, 2012. doi: 10.1091/mbc.E11-06-0537.CrossRefGoogle Scholar
  57. 57.
    Levental, I., P. C. Georges, and P. A. Janmey. Soft biological materials and their impact on cell function. Soft Matter 3(3):299–306, 2007. doi: 10.1039/b610522j.CrossRefGoogle Scholar
  58. 58.
    Levental, K. R., H. Yu, L. Kass, J. N. Lakins, M. Egeblad, J. T. Erler, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139(5):891–906, 2009. doi: 10.1016/j.cell.2009.10.027.CrossRefGoogle Scholar
  59. 59.
    Liu, J., M. L. Gardel, K. Kroy, E. Frey, B. D. Hoffman, J. C. Crocker, et al. Microrheology probes length scale dependent rheology. Phys. Rev. Lett. 96(11):118104, 2006. doi: 10.1103/PhysRevLett.96.118104.CrossRefGoogle Scholar
  60. 60.
    Lu, P., V. M. Weaver, and Z. Werb. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196(4):395–406, 2012. doi: 10.1083/jcb.201102147.CrossRefGoogle Scholar
  61. 61.
    MacKintosh, F. C., J. Käs, and P. A. Janmey. Elasticity of semiflexible biopolymer networks. Phys. Rev. Lett. 75(24):4425, 1995.CrossRefGoogle Scholar
  62. 62.
    Mak, M., R. D. Kamm, and M. H. Zaman. Impact of dimensionality and network disruption on microrheology of cancer cells in 3D environments. PLoS Comput. Biol. 10(11):e1003959, 2014. doi: 10.1371/journal.pcbi.1003959.CrossRefGoogle Scholar
  63. 63.
    Mason, T., K. Ganesan, J. van Zanten, D. Wirtz, and S. Kuo. Particle tracking microrheology of complex fluids. Phys. Rev. Lett. 79(17):3282–3285, 1997. doi: 10.1103/PhysRevLett.79.3282.CrossRefGoogle Scholar
  64. 64.
    Mason, T. G., and D. A. Weitz. Optical measurements of frequency-dependent linear viscoelastic moduli of complex fluids. Phys. Rev. Lett. 74(7):1250–1253, 1995.CrossRefGoogle Scholar
  65. 65.
    Mickel, W., S. Münster, L. M. Jawerth, D. A. Vader, D. A. Weitz, A. P. Sheppard, et al. Robust pore size analysis of filamentous networks from three-dimensional confocal microscopy. Biophys. J. 95(12):6072–6080, 2008. doi: 10.1529/biophysj.108.135939.CrossRefGoogle Scholar
  66. 66.
    Motte, S., and L. J. Kaufman. Strain stiffening in collagen I networks. Biopolymers 99(1):35–46, 2013. doi: 10.1002/bip.22133.CrossRefGoogle Scholar
  67. 67.
    Mouw, J. K., G. Ou, and V. M. Weaver. Extracellular matrix assembly: a multiscale deconstruction. Nat. Rev. Mol. Cell Biol. 15(12):771–785, 2014. doi: 10.1038/nrm3902.CrossRefGoogle Scholar
  68. 68.
    Münster, S., L. M. Jawerth, B. A. Leslie, J. I. Weitz, B. Fabry, and D. A. Weitz. Strain history dependence of the nonlinear stress response of fibrin and collagen networks. Proc. Natl. Acad. Sci. USA 110(30):1–6, 2013. doi: 10.1073/pnas.1222787110.CrossRefGoogle Scholar
  69. 69.
    Ng, M. R., and J. S. Brugge. A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell 16(6):455–457, 2009. doi: 10.1016/j.ccr.2009.11.013.CrossRefGoogle Scholar
  70. 70.
    Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8(2):98–101, 1989.Google Scholar
  71. 71.
    Pathak, A., and S. Kumar. Biophysical regulation of tumor cell invasion: moving beyond matrix stiffness. Integr. Biol. 3(4):267–278, 2011. doi: 10.1039/C0IB00095G.CrossRefGoogle Scholar
  72. 72.
    Patsialou, A., J. J. Bravo-Cordero, Y. Wang, D. Entenberg, H. Liu, M. Clarke, and J. S. Condeelis. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. Intravital 2(2):e25294, 2013. doi: 10.4161/intv.25294.CrossRefGoogle Scholar
  73. 73.
    Pedersen, J. A., and M. A. Swartz. Mechanobiology in the third dimension. Ann. Biomed. Eng. 33(11):1469–1490, 2005. doi: 10.1007/s10439-005-8159-4.CrossRefGoogle Scholar
  74. 74.
    Peterman, E. J. G., F. Gittes, and C. F. Schmidt. Laser-induced heating in optical traps. Biophys. J. 84(February):1308–1316, 2003.CrossRefGoogle Scholar
  75. 75.
    Petrie, R. J., H. Koo, and K. M. Yamada. Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science 345(6200):1062–1065, 2014. doi: 10.1126/science.1256965.CrossRefGoogle Scholar
  76. 76.
    Pickup, M. W., J. K. Mouw, and V. M. Weaver. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15(12):1243–1253, 2014. doi: 10.15252/embr.201439246.CrossRefGoogle Scholar
  77. 77.
    Plodinec, M., M. Loparic, C. A. Monnier, E. C. Obermann, R. Zanetti-Dallenbach, P. Oertle, et al. The nanomechanical signature of breast cancer. Nat. Nano 7(11):757–765, 2012. doi: 10.1038/nnano.2012.167.CrossRefGoogle Scholar
  78. 78.
    Plodinec, M., M. Loparic, C. A. Monnier, E. C. Obermann, R. Zanetti-Dallenbach, P. Oertle, et al. The nanomechanical signature of breast cancer. Nat. Nanotechnol. 7(11):757–765, 2012. doi: 10.1038/nnano.2012.167.CrossRefGoogle Scholar
  79. 79.
    Plotnick, R. E., R. H. Gardner, W. W. Hargrove, K. Prestegaard, and M. Perlmutter. Lacunarity analysis: a general technique for the analysis of spatial patterns. Phys. Rev. E 53(5):5461–5468, 1996. doi: 10.1103/PhysRevE.53.5461.CrossRefGoogle Scholar
  80. 80.
    Provenzano, P. P., K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4(1):38, 2006. doi: 10.1186/1741-7015-4-38.CrossRefGoogle Scholar
  81. 81.
    Raub, C. B., V. Suresh, T. Krasieva, J. Lyubovitsky, J. D. Mih, A. J. Putnam, et al. Noninvasive assessment of collagen gel microstructure and mechanics using multiphoton microscopy. Biophys. J. 92(6):2212–2222, 2007. doi: 10.1529/biophysj.106.097998.CrossRefGoogle Scholar
  82. 82.
    Raub, C. B., J. Unruh, V. Suresh, T. Krasieva, T. Lindmo, E. Gratton, et al. Image correlation spectroscopy of multiphoton images correlates with collagen mechanical properties. Biophys. J. 94(6):2361–2373, 2008. doi: 10.1529/biophysj.107.120006.CrossRefGoogle Scholar
  83. 83.
    Roeder, B. A., K. Kokini, J. E. Sturgis, J. P. Robinson, and S. L. Voytik-Harbin. Tensile mechanical properties of three-dimensional type I collagen extracellular matrices with varied microstructure. J. Biomech. Eng. 124:214–222, 2002. doi: 10.1115/1.1449904.CrossRefGoogle Scholar
  84. 84.
    Schedin, P., and P. J. Keely. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb. Perspect. Biol. 3(1):a003228, 2011. doi: 10.1101/cshperspect.a003228.CrossRefGoogle Scholar
  85. 85.
    Shen, Z. L., M. R. Dodge, H. Kahn, R. Ballarini, and S. J. Eppell. Stress-strain experiments on individual collagen fibrils. Biophys. J. 95(8):3956–3963, 2008. doi: 10.1529/biophysj.107.124602.CrossRefGoogle Scholar
  86. 86.
    Shoulders, M. D., and R. T. Raines. Collagen structure and stability. Annu. Rev. Biochem. 78:929–958, 2009. doi: 10.1146/annurev.biochem.77.032207.120833.CrossRefGoogle Scholar
  87. 87.
    Sollich, P. Rheological constitutive equation for a model of soft glassy materials. Phys. Rev. E 58(1):738–759, 1998. doi: 10.1103/PhysRevE.58.738.CrossRefGoogle Scholar
  88. 88.
    Sollich, P., F. Lequeux, P. Hébraud, and M. Cates. Rheology of soft glassy materials. Phys. Rev. Lett. 78(10):2020–2023, 1997. doi: 10.1103/PhysRevLett.78.2020.CrossRefGoogle Scholar
  89. 89.
    Squires, T. M., and T. G. Mason. Fluid mechanics of microrheology. Annu. Rev. Fluid Mech. 42:413–438, 2010. doi: 10.1146/annurev-fluid-121108-145608.CrossRefGoogle Scholar
  90. 90.
    Staunton, J. R., B. L. Doss, S. Lindsay, and R. Ros. Correlating confocal microscopy and atomic force indentation reveals metastatic cancer cells stiffen during invasion into collagen I matrices. Sci. Rep. 6:19686, 2016. doi: 10.1038/srep19686.CrossRefGoogle Scholar
  91. 91.
    Storm, C., J. J. Pastore, F. MacKintosh, T. Lubensky, and P. A. Jamney. Nonlinear elasticity in biological gels. Nature 435:191–194, 2005. doi: 10.1038/nature03497.1.CrossRefGoogle Scholar
  92. 92.
    Stroka, K. M., H. Jiang, S.-H. Chen, Z. Tong, D. Wirtz, S. X. Sun, and K. Konstantopoulos. Water permeation drives tumor cell migration in confined microenvironments. Cell 157(3):611–623, 2014. doi: 10.1016/j.cell.2014.02.052.CrossRefGoogle Scholar
  93. 93.
    Sun, Y. L., Z. P. Luo, A. Fertala, and K. N. An. Direct quantification of the flexibility of type I collagen monomer. Biochem. Biophys. Res. Commun. 295(2):382–386, 2002. doi: 10.1016/S0006-291X(02)00685-X.CrossRefGoogle Scholar
  94. 94.
    Svoboda, K., and S. M. Block. Biological applications of optical forces. Annu. Rev. Biophys. Biomol. Struct. 23:247–285, 1994. doi: 10.1146/annurev.bb.23.060194.001335.CrossRefGoogle Scholar
  95. 95.
    Tanner, K., and M. M. Gottesman. Beyond 3D culture models of cancer. Sci. Transl. Med. 7(283):283ps9, 2015. doi: 10.1126/scitranslmed.3009367.CrossRefGoogle Scholar
  96. 96.
    Tilbury, K., and P. J. Campagnola. Applications of second-harmonic generation imaging microscopy in ovarian and breast cancer. Perspect. Med. Chem. 7:21–32, 2015. doi: 10.4137/PMC.S13214.Google Scholar
  97. 97.
    Tolle, C. R., T. R. McJunkin, and D. J. Gorsich. An efficient implementation of the gliding box lacunarity algorithm. Physica D 237(3):306–315, 2008. doi: 10.1016/j.physd.2007.09.017.MathSciNetMATHCrossRefGoogle Scholar
  98. 98.
    van Kempen, L. C., D. J. Ruiter, G. N. van Muijen, and L. M. Coussens. The tumor microenvironment: a critical determinant of neoplastic evolution. Eur. J. Cell Biol. 82(11):539–548, 2003. doi: 10.1078/0171-9335-00346.CrossRefGoogle Scholar
  99. 99.
    Wallace, D. G., and J. Rosenblatt. Collagen gel systems for sustained delivery and tissue engineering. Adv. Drug Deliv. Rev. 55(12):1631–1649, 2003.CrossRefGoogle Scholar
  100. 100.
    Weber, F., L. Shen, K. Fukino, A. Patocs, G. L. Mutter, T. Caldes, and C. Eng. Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am. J. Hum. Genet. 78(6):961–972, 2006. doi: 10.1086/504090.CrossRefGoogle Scholar
  101. 101.
    Wenger, M. P. E., L. Bozec, M. A. Horton, and P. Mesquida. Mechanical properties of collagen fibrils. Biophys. J. 93(4):1255–1263, 2007. doi: 10.1529/biophysj.106.103192.CrossRefGoogle Scholar
  102. 102.
    Werb, Z., and P. Lu. The role of stroma in tumor development. Cancer J. 21(4):250–253, 2015. doi: 10.1097/PPO.0000000000000127.CrossRefGoogle Scholar
  103. 103.
    Williams, B. R., R. A. Gelman, D. C. Poppke, and K. A. Piez. Collagen fibril formation. Optimal in vitro conditions and preliminary kinetic results. J. Biol. Chem. 253(18):6578–6585, 1978Google Scholar
  104. 104.
    Wirtz, D. Particle-tracking microrheology of living cells: principles and applications. Ann. Rev. Biophys. 38:301–326, 2009. doi: 10.1146/annurev.biophys.050708.133724.CrossRefGoogle Scholar
  105. 105.
    Wolf, K., M. te Lindert, M. Krause, S. Alexander, J. te Riet, A. L. Willis, et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201(7):1069–1084, 2013. doi: 10.1083/jcb.201210152.CrossRefGoogle Scholar
  106. 106.
    Xu, R., A. Boudreau, and M. J. Bissell. Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices. Cancer Metastasis Rev. 28(1–2):167–176, 2009. doi: 10.1007/s10555-008-9178-z.CrossRefGoogle Scholar
  107. 107.
    Zoumi, A., A. Yeh, and B. J. Tromberg. Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence. Proc. Natl. Acad. Sci. USA 99(17):11014–11019, 2002. doi: 10.1073/pnas.172368799.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society (Outside the U.S.) 2016

Authors and Affiliations

  1. 1.Laboratory of Cell Biology, Center for Cancer ResearchNational Cancer Institute (NIH)BethesdaUSA
  2. 2.Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer ResearchNational Cancer Institute (NIH)BethesdaUSA

Personalised recommendations