Abstract

This report assesses the ability of intrinsic two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) imaging to characterize features associated with the motility and invasive potential of epithelial tumor cells engineered in tissues. Distinct patterns of organization are found both within the cells and the matrix that depend on the adhesive properties of the cells as well as factors attributed to adjacent fibroblasts. TPEF images are analyzed using automated algorithms that reveal unique features in subcellular organization and cell spacing that correlate with the invasive potential. We expect that such features have significant diagnostic potential for basic in vitro studies that aim to improve our understanding of cancer development or response to treatments, and, ultimately can be applied in prognostic evaluation.

© 2010 OSA

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    [CrossRef] [PubMed]
  39. S. Islam, T. E. Carey, G. T. Wolf, M. J. Wheelock, and K. R. Johnson, “Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion,” J. Cell Biol. 135(6), 1643–1654 (1996).
    [CrossRef] [PubMed]
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2010 (1)

W. L. Rice, D. L. Kaplan, I. Georgakoudi, and D. J. S. Hulmes, “Two-photon microscopy for non-invasive, quantitative monitoring of stem cell differentiation,” PLoS ONE 5(4), e10075 (2010).
[CrossRef] [PubMed]

2009 (2)

C. Bayan, J. M. Levitt, E. Miller, D. Kaplan, and I. Georgakoudi, “Fully automated, quantitative, noninvasive assessment of collagen fiber content and organization in thick collagen gels,” J. Appl. Phys. 105(10), 102042 (2009).
[CrossRef]

K. Polyak and R. A. Weinberg, “Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits,” Nat. Rev. Cancer 9(4), 265–273 (2009).
[CrossRef] [PubMed]

2008 (3)

C. Mujat, C. Greiner, A. Baldwin, J. M. Levitt, F. Tian, L. A. Stucenski, M. Hunter, Y. L. Kim, V. Backman, M. Feld, K. Münger, and I. Georgakoudi, “Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells,” Int. J. Cancer 122(2), 363–371 (2008).
[CrossRef] [PubMed]

I. Georgakoudi, W. L. Rice, M. Hronik-Tupaj, and D. L. Kaplan, “Optical spectroscopy and imaging for the noninvasive evaluation of engineered tissues,” Tissue Eng. Part B Rev. 14(4), 321–340 (2008).
[CrossRef] [PubMed]

P. P. Provenzano, K. W. Eliceiri, L. Yan, A. Ada-Nguema, M. W. Conklin, D. R. Inman, and P. J. Keely, “Nonlinear optical imaging of cellular processes in breast cancer,” Microsc. Microanal. 14(6), 532–548 (2008).
[CrossRef] [PubMed]

2007 (3)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[CrossRef] [PubMed]

J. A. Palero, H. S. de Bruijn, A. van der Ploeg van den Heuvel, H. J. C. M. Sterenborg, and H. C. Gerritsen, “Spectrally resolved multiphoton imaging of in vivo and excised mouse skin tissues,” Biophys. J. 93(3), 992–1007 (2007).
[CrossRef] [PubMed]

J. M. Levitt, M. Hunter, C. Mujat, M. McLaughlin-Drubin, K. Münger, and I. Georgakoudi, “Diagnostic cellular organization features extracted from autofluorescence images,” Opt. Lett. 32(22), 3305–3307 (2007).
[CrossRef] [PubMed]

2006 (7)

M. T. Myaing, D. J. MacDonald, and X. Li, “Fiber-optic scanning two-photon fluorescence endoscope,” Opt. Lett. 31(8), 1076–1078 (2006).
[CrossRef] [PubMed]

P. P. Provenzano, 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).
[CrossRef] [PubMed]

G. Christofori, “New signals from the invasive front,” Nature 441(7092), 444–450 (2006).
[CrossRef] [PubMed]

A. Margulis, W. Zhang, A. Alt-Holland, S. Pawagi, P. Prabhu, J. Cao, S. Zucker, L. Pfeiffer, J. Garfield, N. E. Fusenig, and J. A. Garlick, “Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma,” Int. J. Cancer 118(4), 821–831 (2006).
[CrossRef] [PubMed]

K. Schenke-Layland, I. Riemann, O. Damour, U. A. Stock, and K. König, “Two-photon microscopes and in vivo multiphoton tomographs--powerful diagnostic tools for tissue engineering and drug delivery,” Adv. Drug Deliv. Rev. 58(7), 878–896 (2006).
[CrossRef] [PubMed]

W. Zhang, A. Alt-Holland, A. Margulis, Y. Shamis, N. E. Fusenig, U. Rodeck, and J. A. Garlick, “E-cadherin loss promotes the initiation of squamous cell carcinoma invasion through modulation of integrin-mediated adhesion,” J. Cell Sci. 119(2), 283–291 (2006).
[CrossRef] [PubMed]

M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue self-affinity and polarized light scattering in the born approximation: a new model for precancer detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
[CrossRef] [PubMed]

2005 (4)

A. Alt-Holland, W. Zhang, A. Margulis, and J. A. Garlick, “Microenvironmental control of premalignant disease: the role of intercellular adhesion in the progression of squamous cell carcinoma,” Semin. Cancer Biol. 15(2), 84–96 (2005).
[CrossRef] [PubMed]

A. Margulis, W. Zhang, A. Alt-Holland, H. C. Crawford, N. E. Fusenig, and J. A. Garlick, “E-cadherin suppression accelerates squamous cell carcinoma progression in three-dimensional, human tissue constructs,” Cancer Res. 65(5), 1783–1791 (2005).
[CrossRef] [PubMed]

A. Orimo, P. B. Gupta, D. C. Sgroi, F. Arenzana-Seisdedos, T. Delaunay, R. Naeem, V. J. Carey, A. L. Richardson, and R. A. Weinberg, “Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion,” Cell 121(3), 335–348 (2005).
[CrossRef] [PubMed]

L. H. Laiho, S. Pelet, T. M. Hancewicz, P. D. Kaplan, and P. T. So, “Two-photon 3-D mapping of ex vivo human skin endogenous fluorescence species based on fluorescence emission spectra,” J. Biomed. Opt. 10(2), 024016 (2005).
[CrossRef] [PubMed]

2003 (6)

P. Friedl and K. Wolf, “Tumour-cell invasion and migration: diversity and escape mechanisms,” Nat. Rev. Cancer 3(5), 362–374 (2003).
[CrossRef] [PubMed]

J. P. Thiery, “Epithelial-mesenchymal transitions in development and pathologies,” Curr. Opin. Cell Biol. 15(6), 740–746 (2003).
[CrossRef] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
[CrossRef] [PubMed]

N. Noguchi, S. Kawashiri, A. Tanaka, K. Kato, and H. Nakaya, “Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma,” Oral Oncol. 39(3), 240–247 (2003).
[CrossRef] [PubMed]

K. Wolf, I. Mazo, H. Leung, K. Engelke, U. H. von Andrian, E. I. Deryugina, A. Y. Strongin, E. B. Bröcker, and P. Friedl, “Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis,” J. Cell Biol. 160(2), 267–277 (2003).
[CrossRef] [PubMed]

2002 (3)

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7(2), 205–214 (2002).
[CrossRef] [PubMed]

S. Huang, A. A. Heikal, and W. W. Webb, “Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein,” Biophys. J. 82(5), 2811–2825 (2002).
[CrossRef] [PubMed]

A. Zoumi, 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. U.S.A. 99(17), 11014–11019 (2002).
[CrossRef] [PubMed]

2001 (1)

G. Dougherty and G. M. Henebry, “Fractal signature and lacunarity in the measurement of the texture of trabecular bone in clinical CT images,” Med. Eng. Phys. 23(6), 369–380 (2001).
[CrossRef] [PubMed]

2000 (1)

D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell 100(1), 57–70 (2000).
[CrossRef] [PubMed]

1999 (2)

Y. Shimao, K. Nabeshima, T. Inoue, and M. Koono, “Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal carcinoma cells: fibroblasts stimulate migration associated with increased fibronectin production via upregulated TGF-beta1,” Int. J. Cancer 82(3), 449–458 (1999).
[CrossRef] [PubMed]

R. Sedivy, C. Windischberger, K. Svozil, E. Moser, and G. Breitenecker, “Fractal analysis: an objective method for identifying atypical nuclei in dysplastic lesions of the cervix uteri,” Gynecol. Oncol. 75(1), 78–83 (1999).
[CrossRef] [PubMed]

1998 (4)

P. Friedl, K. S. Zänker, and E. B. Bröcker, “Cell migration strategies in 3-D extracellular matrix: differences in morphology, cell matrix interactions, and integrin function,” Microsc. Res. Tech. 43(5), 369–378 (1998).
[CrossRef] [PubMed]

A. J. Einstein, H.-S. Wu, and J. Gil, “Self-Affinity and Lacunarity of Chromatin Texture in Benign and Malignant Breast Epithelial Cell Nuclei,” Phys. Rev. Lett. 80(2), 397–400 (1998).
[CrossRef]

N. E. Fusenig and P. Boukamp, “Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes,” Mol. Carcinog. 23(3), 144–158 (1998).
[CrossRef] [PubMed]

P. So, H. Kim, and I. Kochevar, “Two-Photon deep tissue ex vivo imaging of mouse dermal and subcutaneous structures,” Opt. Express 3(9), 339–350 (1998).
[CrossRef] [PubMed]

1996 (3)

J. M. Schmitt and G. Kumar, “Turbulent nature of refractive-index variations in biological tissue,” Opt. Lett. 21(16), 1310–1312 (1996).
[CrossRef] [PubMed]

S. Islam, T. E. Carey, G. T. Wolf, M. J. Wheelock, and K. R. Johnson, “Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion,” J. Cell Biol. 135(6), 1643–1654 (1996).
[CrossRef] [PubMed]

B. M. Gumbiner, “Cell adhesion: the molecular basis of tissue architecture and morphogenesis,” Cell 84(3), 345–357 (1996).
[CrossRef] [PubMed]

1995 (1)

E. D. Hay, “An overview of epithelio-mesenchymal transformation,” Acta Anat. (Basel) 154(1), 8–20 (1995).
[CrossRef] [PubMed]

1994 (1)

W. Birchmeier and J. Behrens, “Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness,” Biochim. Biophys. Acta 1198(1), 11–26 (1994).
[PubMed]

1991 (1)

K. Vleminckx, L. Vakaet, M. Mareel, W. Fiers, and F. van Roy, “Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role,” Cell 66(1), 107–119 (1991).
[CrossRef] [PubMed]

1990 (1)

P. Boukamp, E. J. Stanbridge, D. Y. Foo, P. A. Cerutti, and N. E. Fusenig, “c-Ha-ras oncogene expression in immortalized human keratinocytes (HaCaT) alters growth potential in vivo but lacks correlation with malignancy,” Cancer Res. 50(9), 2840–2847 (1990).
[PubMed]

1989 (1)

J. Behrens, M. M. Mareel, F. M. Van Roy, and W. Birchmeier, “Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion,” J. Cell Biol. 108(6), 2435–2447 (1989).
[CrossRef] [PubMed]

1988 (2)

A. Nagafuchi and M. Takeichi, “Cell binding function of E-cadherin is regulated by the cytoplasmic domain,” EMBO J. 7(12), 3679–3684 (1988).
[PubMed]

G. P. Dotto, R. A. Weinberg, and A. Ariza, “Malignant transformation of mouse primary keratinocytes by Harvey sarcoma virus and its modulation by surrounding normal cells,” Proc. Natl. Acad. Sci. U.S.A. 85(17), 6389–6393 (1988).
[CrossRef] [PubMed]

1986 (1)

R. F. Voss, “Characterization and Measurement of Random Fractals,” Phys. Scr. T13, 27–32 (1986).
[CrossRef]

1979 (1)

B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals,” J. Biol. Chem. 254(11), 4764–4771 (1979).
[PubMed]

Ada-Nguema, A.

P. P. Provenzano, K. W. Eliceiri, L. Yan, A. Ada-Nguema, M. W. Conklin, D. R. Inman, and P. J. Keely, “Nonlinear optical imaging of cellular processes in breast cancer,” Microsc. Microanal. 14(6), 532–548 (2008).
[CrossRef] [PubMed]

Alt-Holland, A.

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P. P. Provenzano, K. W. Eliceiri, L. Yan, A. Ada-Nguema, M. W. Conklin, D. R. Inman, and P. J. Keely, “Nonlinear optical imaging of cellular processes in breast cancer,” Microsc. Microanal. 14(6), 532–548 (2008).
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P. P. Provenzano, 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).
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Y. Shimao, K. Nabeshima, T. Inoue, and M. Koono, “Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal carcinoma cells: fibroblasts stimulate migration associated with increased fibronectin production via upregulated TGF-beta1,” Int. J. Cancer 82(3), 449–458 (1999).
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B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals,” J. Biol. Chem. 254(11), 4764–4771 (1979).
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C. Bayan, J. M. Levitt, E. Miller, D. Kaplan, and I. Georgakoudi, “Fully automated, quantitative, noninvasive assessment of collagen fiber content and organization in thick collagen gels,” J. Appl. Phys. 105(10), 102042 (2009).
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W. L. Rice, D. L. Kaplan, I. Georgakoudi, and D. J. S. Hulmes, “Two-photon microscopy for non-invasive, quantitative monitoring of stem cell differentiation,” PLoS ONE 5(4), e10075 (2010).
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I. Georgakoudi, W. L. Rice, M. Hronik-Tupaj, and D. L. Kaplan, “Optical spectroscopy and imaging for the noninvasive evaluation of engineered tissues,” Tissue Eng. Part B Rev. 14(4), 321–340 (2008).
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L. H. Laiho, S. Pelet, T. M. Hancewicz, P. D. Kaplan, and P. T. So, “Two-photon 3-D mapping of ex vivo human skin endogenous fluorescence species based on fluorescence emission spectra,” J. Biomed. Opt. 10(2), 024016 (2005).
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N. Noguchi, S. Kawashiri, A. Tanaka, K. Kato, and H. Nakaya, “Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma,” Oral Oncol. 39(3), 240–247 (2003).
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N. Noguchi, S. Kawashiri, A. Tanaka, K. Kato, and H. Nakaya, “Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma,” Oral Oncol. 39(3), 240–247 (2003).
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P. P. Provenzano, K. W. Eliceiri, L. Yan, A. Ada-Nguema, M. W. Conklin, D. R. Inman, and P. J. Keely, “Nonlinear optical imaging of cellular processes in breast cancer,” Microsc. Microanal. 14(6), 532–548 (2008).
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P. P. Provenzano, 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).
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P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7(2), 205–214 (2002).
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Kim, Y. L.

C. Mujat, C. Greiner, A. Baldwin, J. M. Levitt, F. Tian, L. A. Stucenski, M. Hunter, Y. L. Kim, V. Backman, M. Feld, K. Münger, and I. Georgakoudi, “Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells,” Int. J. Cancer 122(2), 363–371 (2008).
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König, K.

K. Schenke-Layland, I. Riemann, O. Damour, U. A. Stock, and K. König, “Two-photon microscopes and in vivo multiphoton tomographs--powerful diagnostic tools for tissue engineering and drug delivery,” Adv. Drug Deliv. Rev. 58(7), 878–896 (2006).
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Y. Shimao, K. Nabeshima, T. Inoue, and M. Koono, “Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal carcinoma cells: fibroblasts stimulate migration associated with increased fibronectin production via upregulated TGF-beta1,” Int. J. Cancer 82(3), 449–458 (1999).
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Laiho, L. H.

L. H. Laiho, S. Pelet, T. M. Hancewicz, P. D. Kaplan, and P. T. So, “Two-photon 3-D mapping of ex vivo human skin endogenous fluorescence species based on fluorescence emission spectra,” J. Biomed. Opt. 10(2), 024016 (2005).
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C. Bayan, J. M. Levitt, E. Miller, D. Kaplan, and I. Georgakoudi, “Fully automated, quantitative, noninvasive assessment of collagen fiber content and organization in thick collagen gels,” J. Appl. Phys. 105(10), 102042 (2009).
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C. Mujat, C. Greiner, A. Baldwin, J. M. Levitt, F. Tian, L. A. Stucenski, M. Hunter, Y. L. Kim, V. Backman, M. Feld, K. Münger, and I. Georgakoudi, “Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells,” Int. J. Cancer 122(2), 363–371 (2008).
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J. M. Levitt, M. Hunter, C. Mujat, M. McLaughlin-Drubin, K. Münger, and I. Georgakoudi, “Diagnostic cellular organization features extracted from autofluorescence images,” Opt. Lett. 32(22), 3305–3307 (2007).
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McLaughlin-Drubin, M.

Miller, E.

C. Bayan, J. M. Levitt, E. Miller, D. Kaplan, and I. Georgakoudi, “Fully automated, quantitative, noninvasive assessment of collagen fiber content and organization in thick collagen gels,” J. Appl. Phys. 105(10), 102042 (2009).
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R. Sedivy, C. Windischberger, K. Svozil, E. Moser, and G. Breitenecker, “Fractal analysis: an objective method for identifying atypical nuclei in dysplastic lesions of the cervix uteri,” Gynecol. Oncol. 75(1), 78–83 (1999).
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C. Mujat, C. Greiner, A. Baldwin, J. M. Levitt, F. Tian, L. A. Stucenski, M. Hunter, Y. L. Kim, V. Backman, M. Feld, K. Münger, and I. Georgakoudi, “Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells,” Int. J. Cancer 122(2), 363–371 (2008).
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J. M. Levitt, M. Hunter, C. Mujat, M. McLaughlin-Drubin, K. Münger, and I. Georgakoudi, “Diagnostic cellular organization features extracted from autofluorescence images,” Opt. Lett. 32(22), 3305–3307 (2007).
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C. Mujat, C. Greiner, A. Baldwin, J. M. Levitt, F. Tian, L. A. Stucenski, M. Hunter, Y. L. Kim, V. Backman, M. Feld, K. Münger, and I. Georgakoudi, “Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells,” Int. J. Cancer 122(2), 363–371 (2008).
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J. M. Levitt, M. Hunter, C. Mujat, M. McLaughlin-Drubin, K. Münger, and I. Georgakoudi, “Diagnostic cellular organization features extracted from autofluorescence images,” Opt. Lett. 32(22), 3305–3307 (2007).
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Nabeshima, K.

Y. Shimao, K. Nabeshima, T. Inoue, and M. Koono, “Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal carcinoma cells: fibroblasts stimulate migration associated with increased fibronectin production via upregulated TGF-beta1,” Int. J. Cancer 82(3), 449–458 (1999).
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N. Noguchi, S. Kawashiri, A. Tanaka, K. Kato, and H. Nakaya, “Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma,” Oral Oncol. 39(3), 240–247 (2003).
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B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals,” J. Biol. Chem. 254(11), 4764–4771 (1979).
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A. Margulis, W. Zhang, A. Alt-Holland, S. Pawagi, P. Prabhu, J. Cao, S. Zucker, L. Pfeiffer, J. Garfield, N. E. Fusenig, and J. A. Garlick, “Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma,” Int. J. Cancer 118(4), 821–831 (2006).
[CrossRef] [PubMed]

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L. H. Laiho, S. Pelet, T. M. Hancewicz, P. D. Kaplan, and P. T. So, “Two-photon 3-D mapping of ex vivo human skin endogenous fluorescence species based on fluorescence emission spectra,” J. Biomed. Opt. 10(2), 024016 (2005).
[CrossRef] [PubMed]

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A. Margulis, W. Zhang, A. Alt-Holland, S. Pawagi, P. Prabhu, J. Cao, S. Zucker, L. Pfeiffer, J. Garfield, N. E. Fusenig, and J. A. Garlick, “Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma,” Int. J. Cancer 118(4), 821–831 (2006).
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M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue self-affinity and polarized light scattering in the born approximation: a new model for precancer detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
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A. Margulis, W. Zhang, A. Alt-Holland, S. Pawagi, P. Prabhu, J. Cao, S. Zucker, L. Pfeiffer, J. Garfield, N. E. Fusenig, and J. A. Garlick, “Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma,” Int. J. Cancer 118(4), 821–831 (2006).
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P. P. Provenzano, K. W. Eliceiri, L. Yan, A. Ada-Nguema, M. W. Conklin, D. R. Inman, and P. J. Keely, “Nonlinear optical imaging of cellular processes in breast cancer,” Microsc. Microanal. 14(6), 532–548 (2008).
[CrossRef] [PubMed]

P. P. Provenzano, 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).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[CrossRef] [PubMed]

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P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7(2), 205–214 (2002).
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W. L. Rice, D. L. Kaplan, I. Georgakoudi, and D. J. S. Hulmes, “Two-photon microscopy for non-invasive, quantitative monitoring of stem cell differentiation,” PLoS ONE 5(4), e10075 (2010).
[CrossRef] [PubMed]

I. Georgakoudi, W. L. Rice, M. Hronik-Tupaj, and D. L. Kaplan, “Optical spectroscopy and imaging for the noninvasive evaluation of engineered tissues,” Tissue Eng. Part B Rev. 14(4), 321–340 (2008).
[CrossRef] [PubMed]

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A. Orimo, P. B. Gupta, D. C. Sgroi, F. Arenzana-Seisdedos, T. Delaunay, R. Naeem, V. J. Carey, A. L. Richardson, and R. A. Weinberg, “Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion,” Cell 121(3), 335–348 (2005).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[CrossRef] [PubMed]

Riemann, I.

K. Schenke-Layland, I. Riemann, O. Damour, U. A. Stock, and K. König, “Two-photon microscopes and in vivo multiphoton tomographs--powerful diagnostic tools for tissue engineering and drug delivery,” Adv. Drug Deliv. Rev. 58(7), 878–896 (2006).
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W. Zhang, A. Alt-Holland, A. Margulis, Y. Shamis, N. E. Fusenig, U. Rodeck, and J. A. Garlick, “E-cadherin loss promotes the initiation of squamous cell carcinoma invasion through modulation of integrin-mediated adhesion,” J. Cell Sci. 119(2), 283–291 (2006).
[CrossRef] [PubMed]

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P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7(2), 205–214 (2002).
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K. Schenke-Layland, I. Riemann, O. Damour, U. A. Stock, and K. König, “Two-photon microscopes and in vivo multiphoton tomographs--powerful diagnostic tools for tissue engineering and drug delivery,” Adv. Drug Deliv. Rev. 58(7), 878–896 (2006).
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Schoener, B.

B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals,” J. Biol. Chem. 254(11), 4764–4771 (1979).
[PubMed]

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R. Sedivy, C. Windischberger, K. Svozil, E. Moser, and G. Breitenecker, “Fractal analysis: an objective method for identifying atypical nuclei in dysplastic lesions of the cervix uteri,” Gynecol. Oncol. 75(1), 78–83 (1999).
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A. Orimo, P. B. Gupta, D. C. Sgroi, F. Arenzana-Seisdedos, T. Delaunay, R. Naeem, V. J. Carey, A. L. Richardson, and R. A. Weinberg, “Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion,” Cell 121(3), 335–348 (2005).
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W. Zhang, A. Alt-Holland, A. Margulis, Y. Shamis, N. E. Fusenig, U. Rodeck, and J. A. Garlick, “E-cadherin loss promotes the initiation of squamous cell carcinoma invasion through modulation of integrin-mediated adhesion,” J. Cell Sci. 119(2), 283–291 (2006).
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Y. Shimao, K. Nabeshima, T. Inoue, and M. Koono, “Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal carcinoma cells: fibroblasts stimulate migration associated with increased fibronectin production via upregulated TGF-beta1,” Int. J. Cancer 82(3), 449–458 (1999).
[CrossRef] [PubMed]

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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[CrossRef] [PubMed]

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So, P. T.

L. H. Laiho, S. Pelet, T. M. Hancewicz, P. D. Kaplan, and P. T. So, “Two-photon 3-D mapping of ex vivo human skin endogenous fluorescence species based on fluorescence emission spectra,” J. Biomed. Opt. 10(2), 024016 (2005).
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J. A. Palero, H. S. de Bruijn, A. van der Ploeg van den Heuvel, H. J. C. M. Sterenborg, and H. C. Gerritsen, “Spectrally resolved multiphoton imaging of in vivo and excised mouse skin tissues,” Biophys. J. 93(3), 992–1007 (2007).
[CrossRef] [PubMed]

Stock, U. A.

K. Schenke-Layland, I. Riemann, O. Damour, U. A. Stock, and K. König, “Two-photon microscopes and in vivo multiphoton tomographs--powerful diagnostic tools for tissue engineering and drug delivery,” Adv. Drug Deliv. Rev. 58(7), 878–896 (2006).
[CrossRef] [PubMed]

Stoller, P.

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7(2), 205–214 (2002).
[CrossRef] [PubMed]

Stoner, G. D.

M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue self-affinity and polarized light scattering in the born approximation: a new model for precancer detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
[CrossRef] [PubMed]

Strongin, A. Y.

K. Wolf, I. Mazo, H. Leung, K. Engelke, U. H. von Andrian, E. I. Deryugina, A. Y. Strongin, E. B. Bröcker, and P. Friedl, “Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis,” J. Cell Biol. 160(2), 267–277 (2003).
[CrossRef] [PubMed]

Stucenski, L. A.

C. Mujat, C. Greiner, A. Baldwin, J. M. Levitt, F. Tian, L. A. Stucenski, M. Hunter, Y. L. Kim, V. Backman, M. Feld, K. Münger, and I. Georgakoudi, “Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells,” Int. J. Cancer 122(2), 363–371 (2008).
[CrossRef] [PubMed]

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R. Sedivy, C. Windischberger, K. Svozil, E. Moser, and G. Breitenecker, “Fractal analysis: an objective method for identifying atypical nuclei in dysplastic lesions of the cervix uteri,” Gynecol. Oncol. 75(1), 78–83 (1999).
[CrossRef] [PubMed]

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A. Nagafuchi and M. Takeichi, “Cell binding function of E-cadherin is regulated by the cytoplasmic domain,” EMBO J. 7(12), 3679–3684 (1988).
[PubMed]

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N. Noguchi, S. Kawashiri, A. Tanaka, K. Kato, and H. Nakaya, “Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma,” Oral Oncol. 39(3), 240–247 (2003).
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Supplementary Material (2)

» Media 1: MOV (4066 KB)     
» Media 2: MOV (3973 KB)     

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Figures (5)

Fig. 1
Fig. 1

TPEF shows E-cadherin deficiency causes individual tumor cell migration. II-4 and H-2K-E-Cad-II-4 cells imaged with 740nm and 800nm excitation light. Scale bar 100µm for 20x and 25µm for 63x. (a), (e) Histology of II-4 and H-2Kd-E-Cad-II-4 cells, respectively, show essential morphological characteristics of SCC variants. (Inset) Higher zoom images of SCC variants. (b), (f) 20x magnification of 2D optical sections of II-4 and H-2Kd-E-Cad-II-4 intrinsic NAD(P)H fluorescence (green) allows visualization of tumor morphology at a marcroscopic scale similar to histology, without fixation or the use of dyes. Fluorescence images confirm H-2Kd-E-Cad-II-4 cells show limited capacity to adhere to one another, while II-4 cells demonstrate cell-cell contact and grow in dense, organized spherical clusters, suggestive of intact E-cadherin function. (c), (g) SHG images from collagen (red) overlaid with NAD(P)H fluorescence shows II-4 cell clusters have delineated borders that are distinct from surrounding collagen (63x magnification). (d), (h) Multiphoton imaging allows for straightforward generation of 3D rendered images, which show II-4 cells forming densely packed, round clusters as well as the diffuse, scattered organization characteristic of H-2Kd-E-Cad-II-4cells.

Fig. 2
Fig. 2

SHG images from collagen suggest adhesion capability and presence of fibroblasts affect local matrix structure. II-4 and H-2K-E-Cad-II-4 cells imaged with 740nm and 800nm excitation light. Scale bar 100µm for 20x and 25µm for 63x. (a), (d) At 63x magnification NAD(P)H fluorescence (green) and SHG from collagen (red) show collagen organization is unique for II-4 and H-2Kd-Ecad II-4 cells. Collagen organization is quantified for sub-images indicated with a white box as discussed in Results section. The respective entropy and orientation index (OI) values of these images are displayed in the upper right corner of the images demonstrating accurate collagen quantification is possible. 20x magnification of (b) II-4 cells, (c) II-4 cells with a high concentration of fibroblasts, (e) H-2Kd-E-Cad-II-4 cells, and (f) H-2Kd-E-Cad-II-4 cells with a high concentration of fibroblasts displays NAD(P)H fluorescence from cells (green) and SHG from collagen (red). II-4 cells organize collagen in a connected trabecular formation while H-2Kd-E-Cad-II-4 cells have diffuse, less structured fiber networks. Once fibroblasts are added, II-4 cell exhibit empty lumens (white arrow) and less structured collagen networks (c). Increased SHG signal is suggestive of increased fiber density.

Media.
Media.

Media 1 (a) 3D rendering of NAD(P)H fluorescence images from II-4 cells shows cells maintain adhesion and form rounded clusters. Media 2 (b) 3D rendering of NAD(P)H fluorescence image from H-2Kd-Ecad II-4 cells shows individual migratory behavior.

Fig. 3
Fig. 3

Co-culture with fibroblasts influences low-grade invasive tumor cells to organize like high-grade invasive tumor cells. Scale bar 100µm for 20x and 25µm for 63x. 2D Optical sections of NAD(P)H autofluorescence (green) and SHG of collagen type I (red) in 3D gel [(a)–(c) and (g)–(i)] and Histology [(d)–(f) and (j)–(l)] of II-4 and H-2Kd-E-Cad-II-4 cells. (a), and (d) II-4 cells organize in tight bundles and do not migrate individually from origin cluster; (g), (j) H-2Kd-E-Cad-II-4 cells do not maintain cell-cell adhesion and migrate individually as lines or hollow spheres; (b), (c) II-4 cells cultured in the presence of (b) 10,000 and (c) 50,000 fibroblasts become enlarged and exhibit H-2Kd-E-Cad-like behavior; (h)–(i) H-2K-E-Cad-II-4 cells cultured in the presence of fibroblasts also become enlarged and maintain individual cell migratory behavior.

Fig. 4
Fig. 4

Low-grade invasive tumor cells, high-grade invasive tumor cells, and fibroblasts in collagen type I gel have distinct frequency domain characteristics. (a) Representative Power Spectral Density (PSD) spectra with respective fits (colored dashed lines) of II-4 cells and H-2Kd-E-Cad-II-4 cells as a function of fibroblast concentration calculated from NAD(P)H autofluorescence images. (b) Box and whisker plot displaying the median and range of Hurst parameters extracted from 25 fields of each cell group. The mean Hurst parameter values, shown with standard deviations in Table 2, are estimated from the slope (β) of the PSD spectra in a range that corresponds to features in the spatial domain of 1.0µm to 7.2µm, which is reflective of fluorescent features on the order of cell organelles and cell-cell spacing. Differences in the Hurst parameter were found from the fits of the PSD spectra between II-4 cells alone and all other groups (p<0.05) indicated by the black star (∗), demonstrating the ability of this method to identify cells with a migratory/invasive phenotype.

Tables (2)

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Table 1 Quantitative effect of fibroblasts on tumor cells in collagen gel

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Table 2 Migratory cell behavior is characterized by higher Hurst parameter values

Equations (2)

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F ( k r ) = A k r β + C
2 H = β 2

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