Abstract

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

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2011 (5)

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]

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]

D. D. Nolte, R. An, J. Turek, and K. Jeong, “Holographic tissue dynamics spectroscopy,” J. Biomed. Opt.16(8), 087004 (2011).
[CrossRef] [PubMed]

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]

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]

2010 (2)

T. A. Lampert and S. E. M. O'Keefe, “A survey of spectrogram track detection algorithms,” Appl. Acoust.71(2), 87–100 (2010).
[CrossRef]

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]

2009 (8)

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]

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]

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]

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]

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]

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]

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]

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]

2008 (8)

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]

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]

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]

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]

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]

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]

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]

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]

2007 (10)

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]

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]

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]

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]

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]

R. Sullivan and C. H. Graham, “Hypoxia-driven selection of the metastatic phenotype,” Cancer Metastasis Rev.26(2), 319–331 (2007).
[CrossRef] [PubMed]

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]

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]

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]

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]

2006 (4)

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).
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Z. Yaqoob, J. Fingler, X. Heng, and C. H. Yang, “Homodyne en face optical coherence tomography,” Opt. Lett.31(12), 1815–1817 (2006).
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J. Zhou, T. Schmid, S. Schnitzer, and B. Brüne, “Tumor hypoxia and cancer progression,” Cancer Lett.237(1), 10–21 (2006).
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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]

2005 (2)

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).
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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).
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2004 (6)

2003 (3)

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).
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W. E. Moerner and D. P. Fromm, “Methods of single-molecule fluorescence spectroscopy and microscopy,” Rev. Sci. Instrum.74(8), 3597–3619 (2003).
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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]

2002 (6)

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).
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M. Laubscher, M. Ducros, B. Karamata, T. Lasser, and R. Salathe, “Video-rate three-dimensional optical coherence tomography,” Opt. Express10(9), 429–435 (2002).
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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).
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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]

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]

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).
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2001 (1)

S. L. Voytik-Harbin, “Three-dimensional extracellular matrix substrates for cell culture,” Methods Cell Biol.63, 561–581 (2001).
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2000 (2)

K. König, “Multiphoton microscopy in life sciences,” J. Microsc.200(2), 83–104 (2000).
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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]

1997 (2)

W. Mueller-Klieser, “Three-dimensional cell cultures: from molecular mechanisms to clinical applications,” Am. J. Physiol.273(4 Pt 1), C1109–C1123 (1997).
[PubMed]

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]

1996 (3)

R. H. Webb, “Confocal optical microscopy,” Rep. Prog. Phys.59(3), 427–471 (1996).
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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).
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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).
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1992 (1)

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).
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1991 (1)

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).
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1989 (1)

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).
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1988 (1)

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]

1987 (1)

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).
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1986 (1)

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).
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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).
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Adams, J.

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]

Ahlgren, U.

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).
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Al-Abd, A. M.

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).
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An, A. J.

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).
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An, R.

D. D. Nolte, R. An, J. Turek, and K. Jeong, “Holographic tissue dynamics spectroscopy,” J. Biomed. Opt.16(8), 087004 (2011).
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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).
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Andreopoulos, B.

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).
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Ashcroft, M.

E. Poon, A. L. Harris, and M. Ashcroft, “Targeting the hypoxia-inducible factor (HIF) pathway in cancer,” Expert Rev. Mol. Med.11, e26 (2009).
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Avilés-Salas, A.

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]

Baldock, R.

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).
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Barbone, D.

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).
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Bender, A.

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]

Bérubé, L. R.

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).
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Boccara, C.

Broaddus, V. C.

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]

Brüne, B.

J. Zhou, T. Schmid, S. Schnitzer, and B. Brüne, “Tumor hypoxia and cancer progression,” Cancer Lett.237(1), 10–21 (2006).
[CrossRef] [PubMed]

Buckman, R.

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]

Cahalan, M. D.

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]

Callaghan, R.

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).
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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).
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Carlson, B. L.

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]

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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]

Castaneda, J.

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).
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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).
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Cazin, L.

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]

Chaikin, P. M.

D. J. Pine, D. A. Weitz, P. M. Chaikin, and E. Herbolzheimer, “Diffusing wave spectroscopy,” Phys. Rev. Lett.60(12), 1134–1137 (1988).
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Chang, T. T.

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).
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Chang, W.

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]

Chiang, G. G.

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).
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Choi, M.-S.

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).
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Cody, N. A. L.

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).
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Cuddihy, M. J.

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).
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Cukierman, E.

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]

Culmsee, C.

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).
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Czarnota, G. J.

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]

D’Arcy, P.

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]

Dalton, W. S.

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).
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Dardousis, K.

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).
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David, L.

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]

Davidson, D.

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]

Del Bene, F.

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).
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Delpy, D. T.

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]

der Wall, E.

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]

Dewhirst, M. W.

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).
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Dittfeld, C.

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).
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Dobrowsky, E.

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]

Doddi, V.

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]

Doss, M.

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]

Drexler, W.

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]

Dubois, A.

Ducros, M.

Dulong, V.

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]

Ebner, R.

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]

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]

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]

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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]

Elliott, P.

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]

Eshleman, J. S.

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]

Farhat, G.

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]

Fayad, W.

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]

Feng, Y.

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]

Fercher, A. F.

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]

Ferguson, D. J. P.

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]

Filali-Mouhim, A.

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]

Fingler, J.

Firbank, M.

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]

Flotte, T.

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]

Forbes, N. S.

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]

Foster, F. S.

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]

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).
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Acta Biomater. (1)

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Figures (8)

Fig. 1
Fig. 1

Differential response spectrograms for 28 different drugs, doses and conditions divided into separate responses for the shell (upper) and core (lower). For each spectrogram, frequency is along the vertical axis from 0.005 Hz to 5 Hz, and time is along the horizontal axis for 6 hour durations after the dose or perturbation is applied (vertical line).

Fig. 2
Fig. 2

Feature masks for spectrogram feature extraction. The time-frequency space is divided into early time (0 to 50 min), mid-time (50 to 150 min) and late time (150 to 350 min), as well as frequency masks that extract the average, low frequency, frequency shift, high frequency and mid-frequency.

Fig. 3
Fig. 3

Generation of a feature vector (represented as a pseudo-color row vector) from a drug-response spectrogram using the feature masks of Fig. 2. Characteristic times and frequencies are shown on the spectrogram. The arrows show the dominant contributions for several feature values. Blue-to-Red colorscale is from −0.6 to +0.6.

Fig. 4
Fig. 4

Feature vectors and similarity matrix for 60 doses and conditions (treating the proliferating shell and the core independently). The ordering is by drug dose, with the shell alternating with the core.

Fig. 5
Fig. 5

Feature vectors and similarity matrix after unsupervised hierarchical clustering (treating shell and core independently).

Fig. 6
Fig. 6

Multidimensional scaling of the data from Fig. 4 displayed in a two-dimensional phenotypic space. The grouping of the drug responses preserves the overall ordering of distances from the similarity matrix of Fig. 5. Physiological responses are overlain in a Venn diagram based on shared features.

Fig. 7
Fig. 7

Shell and core response spectrograms for cytochalasin D at 50 µg/ml. The spectrograms share similar features except for the high-frequency enhancement in the shell that is missing in the core. The colorscale is between −0.7 and +0.7.

Fig. 8
Fig. 8

Apoptotic index vs. shell rank for the top 8 apoptosis-inducing drug doses. The apoptotic index is negative for the core drug response in each case because of the absence of active transport in the hypoxic core.

Tables (2)

Tables Icon

Table 1 Environmental conditions and pharmacological concentrations

Tables Icon

Table 2 Percentage of live/apoptotic/dead cells in 100 µm optical section of 300-600 µm diameter UMR-106 tumor spheroids

Equations (8)

Equations on this page are rendered with MathJax. Learn more.

D( ν,t )= S( ν,t ) S ¯ ( ν, t 0 ) S ¯ ( ν, t 0 )
D( ν,t )= Δν ν 0 ( ν 1+β ν 0 1+β ν 1+β + ν 0 1+β )
V k j = D j ( ν,t ), M k ( ν,t )
D j ( ν,t ), M k ( ν,t ) = 1 N norm p,q D pq j M k,pq
N norm = p,q M pq M pq i,j D pq D pq
S ij = k V k i V k j k V k i V k i k V k j V k j
C= j>i ( | r i r j | d ij ) 2
A i =Re{ M i }Im{ M i } M i =sqrt( V 6 i )sqrt( V 12 i )

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