OSA's Digital Library

Biomedical Optics Express

Biomedical Optics Express

  • Editor: Joseph A. Izatt
  • Vol. 3, Iss. 11 — Nov. 1, 2012
  • pp: 2825–2841

Tissue dynamics spectroscopy for phenotypic profiling of drug effects in three-dimensional culture

David D. Nolte, Ran An, John Turek, and Kwan Jeong  »View Author Affiliations

Biomedical Optics Express, Vol. 3, Issue 11, pp. 2825-2841 (2012)

View Full Text Article

Enhanced HTML    Acrobat PDF (3363 KB)

Browse Journals / Lookup Meetings

Browse by Journal and Year


Lookup Conference Papers

Close Browse Journals / Lookup Meetings

Article Tools



Coherence-gated dynamic light scattering captures cellular dynamics through ultra-low-frequency (0.005–5 Hz) speckle fluctuations and Doppler shifts that encode a broad range of cellular and subcellular motions. The dynamic physiological response of tissues to applied drugs is the basis for a new type of phenotypic profiling for drug screening on multicellular tumor spheroids. Volumetrically resolved tissue-response fluctuation spectrograms act as fingerprints that are segmented through feature masks into high-dimensional feature vectors. Drug-response clustering is achieved through multidimensional scaling with simulated annealing to construct phenotypic drug profiles that cluster drugs with similar responses. Hypoxic vs. normoxic tissue responses present two distinct phenotypes with differentiated responses to environmental perturbations and to pharmacological doses.

© 2012 OSA

OCIS Codes
(110.1650) Imaging systems : Coherence imaging
(170.0170) Medical optics and biotechnology : Medical optics and biotechnology
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(090.1995) Holography : Digital holography

ToC Category:
Biosensors and Molecular Diagnostics

Original Manuscript: July 24, 2012
Revised Manuscript: October 3, 2012
Manuscript Accepted: October 3, 2012
Published: October 15, 2012

David D. Nolte, Ran An, John Turek, and Kwan Jeong, "Tissue dynamics spectroscopy for phenotypic profiling of drug effects in three-dimensional culture," Biomed. Opt. Express 3, 2825-2841 (2012)

Sort:  Author  |  Year  |  Journal  |  Reset  


  1. Y. Feng, T. J. Mitchison, A. Bender, D. W. Young, and J. A. Tallarico, “Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds,” Nat. Rev. Drug Discov.8(7), 567–578 (2009). [CrossRef] [PubMed]
  2. P. J. Keller, F. Pampaloni, and E. H. K. Stelzer, “Life sciences require the third dimension,” Curr. Opin. Cell Biol.18(1), 117–124 (2006). [CrossRef] [PubMed]
  3. F. Pampaloni, E. G. Reynaud, and E. H. K. Stelzer, “The third dimension bridges the gap between cell culture and live tissue,” Nat. Rev. Mol. Cell Biol.8(10), 839–845 (2007). [CrossRef] [PubMed]
  4. L. Gaedtke, L. Thoenes, C. Culmsee, B. Mayer, and E. Wagner, “Proteomic analysis reveals differences in protein expression in spheroid versus monolayer cultures of low-passage colon carcinoma cells,” J. Proteome Res.6(11), 4111–4118 (2007). [CrossRef] [PubMed]
  5. J. Poland, P. Sinha, A. Siegert, M. Schnölzer, U. Korf, and S. Hauptmann, “Comparison of protein expression profiles between monolayer and spheroid cell culture of HT-29 cells revealed fragmentation of CK18 in three-dimensional cell culture,” Electrophoresis23(7-8), 1174–1184 (2002). [CrossRef] [PubMed]
  6. T. T. Chang and M. Hughes-Fulford, “Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes,” Tissue Eng. Part A15(3), 559–567 (2009). [CrossRef] [PubMed]
  7. N. A. L. Cody, M. Zietarska, A. Filali-Mouhim, D. M. Provencher, A. M. Mes-Masson, and P. N. Tonin, “Influence of monolayer, spheroid, and tumor growth conditions on chromosome 3 gene expression in tumorigenic epithelial ovarian cancer cell lines,” BMC Med. Genomics1(1), 34 (2008). [CrossRef] [PubMed]
  8. K. Dardousis, C. Voolstra, M. Roengvoraphoj, A. Sekandarzad, S. Mesghenna, J. Winkler, Y. Ko, J. Hescheler, and A. Sachinidis, “Identification of differentially expressed genes involved in the formation of multicellular tumor spheroids by HT-29 colon carcinoma cells,” Mol. Ther.15(1), 94–102 (2007). [CrossRef] [PubMed]
  9. L. David, V. Dulong, D. Le Cerf, L. Cazin, M. Lamacz, and J. P. Vannier, “Hyaluronan hydrogel: an appropriate three-dimensional model for evaluation of anticancer drug sensitivity,” Acta Biomater.4(2), 256–263 (2008). [CrossRef] [PubMed]
  10. I. Serebriiskii, R. Castelló-Cros, A. Lamb, E. A. Golemis, and E. Cukierman, “Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells,” Matrix Biol.27(6), 573–585 (2008). [CrossRef] [PubMed]
  11. A. Frankel, R. Buckman, and R. S. Kerbel, “Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids,” Cancer Res.57(12), 2388–2393 (1997). [PubMed]
  12. L. A. Hazlehurst, T. H. Landowski, and W. S. Dalton, “Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death,” Oncogene22(47), 7396–7402 (2003). [CrossRef] [PubMed]
  13. J. Friedrich, W. Eder, J. Castaneda, M. Doss, E. Huber, R. Ebner, and L. A. Kunz-Schughart, “A reliable tool to determine cell viability in complex 3-d culture: the acid phosphatase assay,” J. Biomol. Screen.12(7), 925–937 (2007). [CrossRef] [PubMed]
  14. W. Mueller-Klieser, “Three-dimensional cell cultures: from molecular mechanisms to clinical applications,” Am. J. Physiol.273(4 Pt 1), C1109–C1123 (1997). [PubMed]
  15. A. Frankel, S. Man, P. Elliott, J. Adams, and R. S. Kerbel, “Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341,” Clin. Cancer Res.6(9), 3719–3728 (2000). [PubMed]
  16. D. Barbone, T. M. Yang, J. R. Morgan, G. Gaudino, and V. C. Broaddus, “Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids,” J. Biol. Chem.283(19), 13021–13030 (2008). [CrossRef] [PubMed]
  17. J. S. Eshleman, B. L. Carlson, A. C. Mladek, B. D. Kastner, K. L. Shide, and J. N. Sarkaria, “Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy,” Cancer Res.62(24), 7291–7297 (2002). [PubMed]
  18. A. L. Howes, G. G. Chiang, E. S. Lang, C. B. Ho, G. Powis, K. Vuori, and R. T. Abraham, “The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures,” Mol. Cancer Ther.6(9), 2505–2514 (2007). [CrossRef] [PubMed]
  19. K. Jeong, L. Peng, D. D. Nolte, and M. R. Melloch, “Fourier-domain holography in photorefractive quantum-well films,” Appl. Opt.43(19), 3802–3811 (2004). [CrossRef] [PubMed]
  20. P. Yu, L. Peng, M. Mustata, J. J. Turek, M. R. Melloch, and D. D. Nolte, “Time-dependent speckle in holographic optical coherence imaging and the health of tumor tissue,” Opt. Lett.29(1), 68–70 (2004). [CrossRef] [PubMed]
  21. K. Jeong, L. Peng, J. J. Turek, M. R. Melloch, and D. D. Nolte, “Fourier-domain holographic optical coherence imaging of tumor spheroids and mouse eye,” Appl. Opt.44(10), 1798–1805 (2005). [CrossRef] [PubMed]
  22. K. Jeong, J. J. Turek, and D. D. Nolte, “Fourier-domain digital holographic optical coherence imaging of living tissue,” Appl. Opt.46(22), 4999–5008 (2007). [CrossRef] [PubMed]
  23. P. Yu, M. Mustata, L. Peng, J. J. Turek, M. R. Melloch, P. M. French, and D. D. Nolte, “Holographic optical coherence imaging of rat osteogenic sarcoma tumor spheroids,” Appl. Opt.43(25), 4862–4873 (2004). [CrossRef] [PubMed]
  24. A. Dubois, K. Grieve, G. Moneron, R. Lecaque, L. Vabre, and C. Boccara, “Ultrahigh-resolution full-field optical coherence tomography,” Appl. Opt.43(14), 2874–2883 (2004). [CrossRef] [PubMed]
  25. M. Laubscher, M. Ducros, B. Karamata, T. Lasser, and R. Salathe, “Video-rate three-dimensional optical coherence tomography,” Opt. Express10(9), 429–435 (2002). [PubMed]
  26. Z. Yaqoob, J. Fingler, X. Heng, and C. H. Yang, “Homodyne en face optical coherence tomography,” Opt. Lett.31(12), 1815–1817 (2006). [CrossRef] [PubMed]
  27. A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,” Rep. Prog. Phys.66(2), 239–303 (2003). [CrossRef]
  28. D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991). [CrossRef] [PubMed]
  29. A. M. Al-Abd, J.-H. Lee, S. Y. Kim, N. Kun, and H.-J. Kuh, “Novel application of multicellular layers culture for in situ evaluation of cytotoxicity and penetration of paclitaxel,” Cancer Sci.99(2), 423–431 (2008). [CrossRef] [PubMed]
  30. M.-S. Choi, S.-H. Kim, and H.-J. Kuh, “Penetration of paclitaxel and 5-fluorouracil in multicellular layers of human colorectal cancer cells,” Oncol. Rep.25(3), 863–870 (2011). [PubMed]
  31. J. Friedrich, C. Seidel, R. Ebner, and L. A. Kunz-Schughart, “Spheroid-based drug screen: considerations and practical approach,” Nat. Protoc.4(3), 309–324 (2009). [CrossRef] [PubMed]
  32. L. A. Kunz-Schughart, J. P. Freyer, F. Hofstaedter, and R. Ebner, “The use of 3-D cultures for high-throughput screening: the multicellular spheroid model,” J. Biomol. Screen.9(4), 273–285 (2004). [CrossRef] [PubMed]
  33. J. Lee, M. J. Cuddihy, and N. A. Kotov, “Three-dimensional cell culture matrices: state of the art,” Tissue Eng. Part B Rev.14(1), 61–86 (2008). [CrossRef] [PubMed]
  34. S. L. Voytik-Harbin, “Three-dimensional extracellular matrix substrates for cell culture,” Methods Cell Biol.63, 561–581 (2001). [CrossRef] [PubMed]
  35. W. E. Moerner and D. P. Fromm, “Methods of single-molecule fluorescence spectroscopy and microscopy,” Rev. Sci. Instrum.74(8), 3597–3619 (2003). [CrossRef]
  36. R. H. Webb, “Confocal optical microscopy,” Rep. Prog. Phys.59(3), 427–471 (1996). [CrossRef]
  37. M. D. Cahalan, I. Parker, S. H. Wei, and M. J. Miller, “Two-photon tissue imaging: seeing the immune system in a fresh light,” Nat. Rev. Immunol.2(11), 872–880 (2002). [CrossRef] [PubMed]
  38. K. König, “Multiphoton microscopy in life sciences,” J. Microsc.200(2), 83–104 (2000). [CrossRef] [PubMed]
  39. J. Sharpe, U. Ahlgren, P. Perry, B. Hill, A. Ross, J. Hecksher-Sørensen, R. Baldock, and D. Davidson, “Optical projection tomography as a tool for 3D microscopy and gene expression studies,” Science296(5567), 541–545 (2002). [CrossRef] [PubMed]
  40. J. Huisken, J. Swoger, F. Del Bene, J. Wittbrodt, and E. H. K. Stelzer, “Optical sectioning deep inside live embryos by selective plane illumination microscopy,” Science305(5686), 1007–1009 (2004). [CrossRef] [PubMed]
  41. F. Hirschhaeuser, H. Menne, C. Dittfeld, J. West, W. Mueller-Klieser, and L. A. Kunz-Schughart, “Multicellular tumor spheroids: an underestimated tool is catching up again,” J. Biotechnol.148(1), 3–15 (2010). [CrossRef] [PubMed]
  42. L. R. Bérubé, K. Harasiewicz, F. S. Foster, E. Dobrowsky, M. D. Sherar, and A. M. Rauth, “Use of a high frequency ultrasound microscope to image the action of 2-nitroimidazoles in multicellular spheroids,” Br. J. Cancer65(5), 633–640 (1992). [CrossRef] [PubMed]
  43. M. D. Sherar, M. B. Noss, and F. S. Foster, “Ultrasound backscatter microscopy images the internal structure of living tumour spheroids,” Nature330(6147), 493–495 (1987). [CrossRef] [PubMed]
  44. D. D. Nolte, R. An, J. Turek, and K. Jeong, “Tissue dynamics spectroscopy for three-dimensional tissue-based drug screening,” J Lab Autom16(6), 431–442 (2011). [CrossRef] [PubMed]
  45. F. C. MacKintosh and S. John, “Diffusing-wave spectroscopy and multiple scattering of light in correlated random media,” Phys. Rev. B Condens. Matter40(4), 2383–2406 (1989). [CrossRef] [PubMed]
  46. D. J. Pine, D. A. Weitz, P. M. Chaikin, and E. Herbolzheimer, “Diffusing wave spectroscopy,” Phys. Rev. Lett.60(12), 1134–1137 (1988). [CrossRef] [PubMed]
  47. T. Katsuda and T. Maruyama, “Chemical-Kinetics Model for the Growth of a Multicellular Tumor Spheroid,” J. Chem. Eng. of Jpn42(3), 198–203 (2009). [CrossRef]
  48. R. Venkatasubramanian, M. A. Henson, and N. S. Forbes, “Incorporating energy metabolism into a growth model of multicellular tumor spheroids,” J. Theor. Biol.242(2), 440–453 (2006). [CrossRef] [PubMed]
  49. S. Rodríguez-Enríquez, J. C. Gallardo-Pérez, A. Avilés-Salas, A. Marín-Hernández, L. Carreño-Fuentes, V. Maldonado-Lagunas, and R. Moreno-Sánchez, “Energy metabolism transition in multi-cellular human tumor spheroids,” J. Cell. Physiol.216(1), 189–197 (2008). [CrossRef] [PubMed]
  50. J. P. Freyer and R. M. Sutherland, “Regulation of growth saturation and development of necrosis in EMT6/Ro multicellular spheroids by the glucose and oxygen supply,” Cancer Res.46(7), 3504–3512 (1986). [PubMed]
  51. K. Groebe and W. Mueller-Klieser, “On the relation between size of necrosis and diameter of tumor spheroids,” Int. J. Radiat. Oncol. Biol. Phys.34(2), 395–401 (1996). [CrossRef] [PubMed]
  52. M. J. Tindall and C. P. Please, “Modelling the cell cycle and cell movement in multicellular tumour spheroids,” Bull. Math. Biol.69(4), 1147–1165 (2007). [CrossRef] [PubMed]
  53. R. J. Gillies and R. A. Gatenby, “Hypoxia and adaptive landscapes in the evolution of carcinogenesis,” Cancer Metastasis Rev.26(2), 311–317 (2007). [CrossRef] [PubMed]
  54. J. Zhou, T. Schmid, S. Schnitzer, and B. Brüne, “Tumor hypoxia and cancer progression,” Cancer Lett.237(1), 10–21 (2006). [CrossRef] [PubMed]
  55. L. I. Cardenas-Navia, R. A. Richardson, and M. W. Dewhirst, “Targeting the molecular effects of a hypoxic tumor microenvironment,” Front. Biosci.12(8-12), 4061–4078 (2007). [CrossRef] [PubMed]
  56. P. Hargrave, P. W. Nicholson, D. T. Delpy, and M. Firbank, “Optical properties of multicellular tumour spheroids,” Phys. Med. Biol.41(6), 1067–1072 (1996). [CrossRef] [PubMed]
  57. J. R. Mourant, T. M. Johnson, V. Doddi, and J. P. Freyer, “Angular dependent light scattering from multicellular spheroids,” J. Biomed. Opt.7(1), 93–99 (2002). [CrossRef] [PubMed]
  58. D. D. Nolte, K. Jeong, P. M. W. French, and J. J. Turek, “Holographic optical coherence imaging,” in Optical Coherence Tomography: Technology and Applications, J. F. A. W. Drexler, ed. (Springer Verlag, 2008).
  59. D. D. Nolte, R. An, J. Turek, and K. Jeong, “Holographic tissue dynamics spectroscopy,” J. Biomed. Opt.16(8), 087004 (2011). [CrossRef] [PubMed]
  60. E. Ifeachor and B. Jervis, Digital Signal Processing: a Practical Approach (Prentice Hall, 2001).
  61. R. A. Johnson, Applied Multivariate Statistical Analysis (Prentice Hall, 2001).
  62. B. Andreopoulos, A. J. An, X. G. Wang, and M. Schroeder, “A roadmap of clustering algorithms: finding a match for a biomedical application,” Brief. Bioinform.10(3), 297–314 (2009). [CrossRef] [PubMed]
  63. T. A. Lampert and S. E. M. O'Keefe, “A survey of spectrogram track detection algorithms,” Appl. Acoust.71(2), 87–100 (2010). [CrossRef]
  64. W. Fayad, L. Rickardson, C. Haglund, M. H. Olofsson, P. D’Arcy, R. Larsson, S. Linder, and M. Fryknäs, “Identification of agents that induce apoptosis of multicellular tumour spheroids: enrichment for mitotic inhibitors with hydrophobic properties,” Chem. Biol. Drug Des.78(4), 547–557 (2011). [CrossRef] [PubMed]
  65. H. R. Mellor, D. J. P. Ferguson, and R. Callaghan, “A model of quiescent tumour microregions for evaluating multicellular resistance to chemotherapeutic drugs,” Br. J. Cancer93(3), 302–309 (2005). [CrossRef] [PubMed]
  66. M. A. Vooijs, E. H. Gort, A. J. Groot, E. der Wall, and P. J. van Diest, “Hypoxic regulation of metastasis via hypoxia-inducible factors,” Curr. Mol. Med.8(1), 60–67 (2008). [CrossRef] [PubMed]
  67. M. W. Klymkowsky and P. Savagner, “Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe,” Am. J. Pathol.174(5), 1588–1593 (2009). [CrossRef] [PubMed]
  68. R. Sullivan and C. H. Graham, “Hypoxia-driven selection of the metastatic phenotype,” Cancer Metastasis Rev.26(2), 319–331 (2007). [CrossRef] [PubMed]
  69. W. Yan, Y. Fu, D. Tian, J. Z. Liao, M. Liu, B. Wang, L. M. Xia, Q. Zhu, and M. Luo, “PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells,” Biochem. Biophys. Res. Commun.382(3), 631–636 (2009). [CrossRef] [PubMed]
  70. G. Farhat, A. Mariampillai, V. X. D. Yang, G. J. Czarnota, and M. C. Kolios, “Detecting apoptosis using dynamic light scattering with optical coherence tomography,” J. Biomed. Opt.16(7), 070505 (2011). [CrossRef] [PubMed]
  71. E. Poon, A. L. Harris, and M. Ashcroft, “Targeting the hypoxia-inducible factor (HIF) pathway in cancer,” Expert Rev. Mol. Med.11, e26 (2009). [CrossRef] [PubMed]

Cited By

Alert me when this paper is cited

OSA is able to provide readers links to articles that cite this paper by participating in CrossRef's Cited-By Linking service. CrossRef includes content from more than 3000 publishers and societies. In addition to listing OSA journal articles that cite this paper, citing articles from other participating publishers will also be listed.

« Previous Article  |  Next Article »

OSA is a member of CrossRef.

CrossCheck Deposited