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

1. G. Christofori, “New signals from the invasive front,” Nature 441(7092), 444–450 (2006). [CrossRef] [PubMed]
2. 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]
3. 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]
4. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell 100(1), 57–70 (2000). [CrossRef] [PubMed]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. R. F. Voss, “Characterization and Measurement of Random Fractals,” Phys. Scr. T13, 27–32 (1986). [CrossRef]
21. 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]
22. 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]
23. 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]
24. B. Mandelbrot, The Fractal Geometry of Nature (W.H. Freeman and Company, New York, 2000).
25. 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]
26. 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]
27. 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]
28. B. M. Gumbiner, “Cell adhesion: the molecular basis of tissue architecture and morphogenesis,” Cell 84(3), 345–357 (1996). [CrossRef] [PubMed]
29. 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]
30. 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]
31. 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]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
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]
40. E. D. Hay, “An overview of epithelio-mesenchymal transformation,” Acta Anat. (Basel) 154(1), 8–20 (1995). [CrossRef] [PubMed]
41. 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]
42. J. M. Schmitt and G. Kumar, “Turbulent nature of refractive-index variations in biological tissue,” Opt. Lett. 21(16), 1310–1312 (1996). [CrossRef] [PubMed]
43. 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]
44. 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]
45. 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]
46. 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]
47. 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]
48. P. Friedl and K. Wolf, “Tumour-cell invasion and migration: diversity and escape mechanisms,” Nat. Rev. Cancer 3(5), 362–374 (2003). [CrossRef] [PubMed]
49. J. P. Thiery, “Epithelial-mesenchymal transitions in development and pathologies,” Curr. Opin. Cell Biol. 15(6), 740–746 (2003). [CrossRef] [PubMed]
50. 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]

Acta Anat. (Basel)

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

Adv. Drug Deliv. Rev.

• 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]

Biochim. Biophys. Acta

• 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]

Biophys. J.

• 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]
• 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]

BMC Med.

• 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]

Cancer Res.

• 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]
• 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]

Cell

• 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]
• D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell 100(1), 57–70 (2000). [CrossRef] [PubMed]
• 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]
• B. M. Gumbiner, “Cell adhesion: the molecular basis of tissue architecture and morphogenesis,” Cell 84(3), 345–357 (1996). [CrossRef] [PubMed]

Curr. Opin. Cell Biol.

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

EMBO J.

• 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]

Gynecol. Oncol.

• 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]

Int. J. Cancer

• 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]
• 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]
• 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]

J. Appl. Phys.

• 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]

J. Biol. Chem.

• 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]

J. Biomed. Opt.

• 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]
• 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]

J. Cell Biol.

• 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]
• 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]
• 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]

J. Cell Sci.

• 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]

Med. Eng. Phys.

• 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]

Microsc. Microanal.

• 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]

Microsc. Res. Tech.

• 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]

Mol. Carcinog.

• 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]

Nat. Biotechnol.

• 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]

Nat. Rev. Cancer

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

Nature

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

Opt. Express

• 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]

Opt. Lett.

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

Oral Oncol.

• 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]

Phys. Rev. Lett.

• 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]
• 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]

Phys. Scr.

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

PLoS ONE

• 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]

Proc. Natl. Acad. Sci. U.S.A.

• 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]
• 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]
• 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]
• 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]

Semin. Cancer Biol.

• 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]

Tissue Eng. Part B Rev.

• 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]

Other

• B. Mandelbrot, The Fractal Geometry of Nature (W.H. Freeman and Company, New York, 2000).

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