Abstract
Application of two-photon microscopy (TPM) to translational and clinical cancer research has burgeoned over the last several years, as several avenues of pre-clinical research have come to fruition. In this review, we focus on two forms of TPM—two-photon excitation fluorescence microscopy, and second harmonic generation microscopy—as they have been used for investigating cancer pathology in ex vivo and in vivo human tissue. We begin with discussion of two-photon theory and instrumentation particularly as applicable to cancer research, followed by an overview of some of the relevant cancer research literature in areas that include two-photon imaging of human tissue biopsies, human skin in vivo, and the rapidly developing technology of two-photon microendoscopy. We believe these and other evolving two-photon methodologies will continue to help translate cancer research from the bench to the bedside, and ultimately bring minimally invasive methods for cancer diagnosis and treatment to therapeutic reality.
Similar content being viewed by others
References
Bahlmann, K., P. T. So, M. Kirber, R. Reich, B. Kosicki, W. McGonagle, and K. Bellve. Multifocal multiphoton microscopy (MMM) at a frame rate beyond 600 Hz. Opt. Express 15:10991–10998, 2007.
Bao, H., A. Boussioutas, J. Reynolds, S. Russell, and M. Gu. Imaging of goblet cells as a marker for intestinal metaplasia of the stomach by one-photon and two-photon fluorescence endomicroscopy. J. Biomed. Opt. 14:064031, 2009.
Bastiaens, P. I., and A. Squire. Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell. Trends Cell Biol. 9:48–52, 1999.
Beerling, E., L. Ritsma, N. Vrisekoop, P. W. Derksen, and J. van Rheenen. Intravital microscopy: new insights into metastasis of tumors. J. Cell Sci. 124:299–310, 2011.
Bewersdorf, J., A. Egner, and S. W. Hell. Multifocal Multi-Photon Microscopy. In: Handbook of Biological Confocal Microscopy, edited by J. B. Pawley. New York: Springer, 2006, pp. 550–560.
Bewersdorf, J., R. Pick, and S. W. Hell. Multifocal multiphoton microscopy. Opt. Lett. 23:655–657, 1998.
Breunig, H. G., H. Studier, and K. Konig. Multiphoton excitation characteristics of cellular fluorophores of human skin in vivo. Opt. Express 18:7857–7871, 2010.
Brown, E., T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat. Med. 9:796–800, 2003.
Campagnola, P. Second harmonic generation imaging microscopy: applications to diseases diagnostics. Anal. Chem. 83:3224–3231, 2011.
Campagnola, P. J., and L. M. Loew. Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms. Nat. Biotechnol. 21:1356–1360, 2003.
Campagnola, P. J., A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler. Three-dimensional high-resolution second-harmonic generation imaging of endogenous structural proteins in biological tissues. Biophys. J. 82:493–508, 2002.
Campagnola, P. J., M. D. Wei, A. Lewis, and L. M. Loew. High-resolution nonlinear optical imaging of live cells by second harmonic generation. Biophys. J. 77:3341–3349, 1999.
Chance, B., 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. 254:4764–4771, 1979.
Chang, Y. C., J. Y. Ye, T. P. Thomas, Z. Cao, A. Kotlyar, E. R. Tkaczyk, J. R. Baker, Jr, and T. B. Norris. Fiber-optic multiphoton flow cytometry in whole blood and in vivo. J. Biomed. Opt. 15:047004, 2010.
Chen, J., A. Lee, J. Zhao, H. Wang, H. Lui, D. I. McLean, and H. Zeng. Spectroscopic characterization and microscopic imaging of extracted and in situ cutaneous collagen and elastic tissue components under two-photon excitation. Skin. Res. Technol. 15:418–426, 2009.
Chen, Y., and A. Periasamy. Characterization of two-photon excitation fluorescence lifetime imaging microscopy for protein localization. Microsc. Res. Tech. 63:72–80, 2004.
Chen, J., S. Zhuo, G. Chen, J. Yan, H. Yang, N. Liu, L. Zheng, X. Jiang, and S. Xie. Establishing diagnostic features for identifying the mucosa and submucosa of normal and cancerous gastric tissues by multiphoton microscopy. Gastrointest. Endosc. 73:802–807, 2011.
Cicchi, R., A. Crisci, A. Cosci, G. Nesi, D. Kapsokalyvas, S. Giancane, M. Carini, and F. S. Pavone. Time- and spectral-resolved two-photon imaging of healthy bladder mucosa and carcinoma in situ. Opt. Express 18:3840–3849, 2010.
Condeelis, J., and J. E. Segall. Intravital imaging of cell movement in tumours. Nat. Rev. Cancer 3:921–930, 2003.
Conklin, M. W., J. C. Eickhoff, K. M. Riching, C. A. Pehlke, K. W. Eliceiri, P. P. Provenzano, A. Friedl, and P. J. Keely. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178:1221–1232, 2011.
Conklin, M. W., P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely. Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast. Cell Biochem. Biophys. 53:145–157, 2009.
Cox, G., E. Kable, A. Jones, I. Fraser, F. Manconi, and M. D. Gorrell. 3-dimensional imaging of collagen using second harmonic generation. J. Struct. Biol. 141:53–62, 2003.
De Giorgi, V., D. Massi, S. Sestini, R. Cicchi, F. S. Pavone, and T. Lotti. Combined non-linear laser imaging (two-photon excitation fluorescence microscopy, fluorescence lifetime imaging microscopy, multispectral multiphoton microscopy) in cutaneous tumours: first experiences. J. Eur. Acad. Dermatol. Venereol. (JEADV) 23:314–316, 2009.
Dela Cruz, J. M., J. D. McMullen, R. M. Williams, and W. R. Zipfel. Feasibility of using multiphoton excited tissue autofluorescence for in vivo human histopathology. Biomed. Opt. Express 1:1320–1330, 2010.
Denk, W., J. H. Strickler, and W. W. Webb. Two-photon laser scanning fluorescence microscopy. Science 248:73–76, 1990.
Dimitrow, E., I. Riemann, A. Ehlers, M. J. Koehler, J. Norgauer, P. Elsner, K. Konig, and M. Kaatz. Spectral fluorescence lifetime detection and selective melanin imaging by multiphoton laser tomography for melanoma diagnosis. Exp. Dermatol. 18:509–515, 2009.
Dimitrow, E., M. Ziemer, M. J. Koehler, J. Norgauer, K. Konig, P. Elsner, and M. Kaatz. Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma. J. Invest. Dermatol. 129:1752–1758, 2009.
Dong, C. Y., and P. J. Campagnola. Optical diagnostics of tissue pathology by multiphoton microscopy. Expert Opin. Med. Diag. 4:519–529, 2010.
Ericson, M. B., C. Simonsson, S. Guldbrand, C. Ljungblad, J. Paoli, and M. Smedh. Two-photon laser-scanning fluorescence microscopy applied for studies of human skin. J. Biophotonics 1:320–330, 2008.
Fine, S., and W. P. Hansen. Optical second harmonic generation in biological systems. Appl. Opt. 10:2350–2353, 1971.
Fischer, F., B. Volkmer, S. Puschmann, R. Greinert, W. Breitbart, J. Kiefer, and R. Wepf. Risk estimation of skin damage due to ultrashort pulsed, focused near-infrared laser irradiation at 800 nm. J. Biomed. Opt. 13:041320, 2008.
Flusberg, B. A., E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer. Fiber-optic fluorescence imaging. Nat. Methods 2:941–950, 2005.
Freund, I., and M. Deutsch. Macroscopic polarity of connective tissue is due to discrete polar structures. Biopolymers 25:601–606, 1986.
Fricke, M., and T. Nielsen. Two-dimensional imaging without scanning by multifocal multiphoton microscopy. Appl. Opt. 44:2984–2988, 2005.
Fu, L., and M. Gu. Fibre-optic nonlinear optical microscopy and endoscopy. J. Microsc. 226:195–206, 2007.
Fukumura, D., D. G. Duda, L. L. Munn, and R. K. Jain. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation 17:206–225, 2010.
Gatesman Ammer, A., K. E. Hayes, K. H. Martin, L. Zhang, G. A. Spirou, and S. A. Weed. Multi-photon imaging of tumor cell invasion in an orthotopic mouse model of oral squamous cell carcinoma. J. Vis. Exp. 53:e2941, 2011.
Ghajar, C. M., and M. J. Bissell. Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging. Histochem. Cell Biol. 130:1105–1118, 2008.
Goppert-Meyer, M. Uber Elementarakte mit zwei Quantensprungen. Gottinger Dissertation. Ann. Phys. 9:273–294, 1931.
Gu, M., H. C. Bao, and J. L. Li. Cancer-cell microsurgery using nonlinear optical endomicroscopy. J. Biomed. Opt. 15:050502, 2010.
Guo, Y., P. P. Ho, A. Tirksliunas, F. Liu, and R. R. Alfano. Optical harmonic generation from animal tissues by the use of picosecond and femtosecond laser pulses. Appl. Opt. 35:6810–6813, 1996.
Guo, Y., H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano. Subsurface tumor progression investigated by noninvasive optical second harmonic tomography. Proc. Natl Acad. Sci. USA 96:10854–10856, 1999.
Han, X., and E. Brown. Measurement of the ratio of forward-propagating to back-propagating second harmonic signal using a single objective. Opt. Express 18:10538–10550, 2010.
Han, X., R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown. Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma. Opt. Express 16:1846–1859, 2008.
Hanson, K. M., and C. J. Bardeen. Application of nonlinear optical microscopy for imaging skin. Photochem. Photobiol. 85:33–44, 2009.
He, W., H. Wang, L. C. Hartmann, J. X. Cheng, and P. S. Low. In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry. Proc. Natl Acad. Sci. USA 104:11760–11765, 2007.
Hompland, T., A. Erikson, M. Lindgren, T. Lindmo, and C. de Lange Davies. Second-harmonic generation in collagen as a potential cancer diagnostic parameter. J. Biomed. Opt.. 13:054050, 2008.
Huang, X., I. H. El-Sayed, W. Qian, and M. A. El-Sayed. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J. Am. Chem. Soc. 128:2115–2120, 2006.
Huang, S., A. A. Heikal, and W. W. Webb. Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein. Biophys. J. 82:2811–2825, 2002.
Huang, Z., Z. Li, R. Chen, J. Lin, Y. Li, and C. Li. In vitro imaging of thyroid tissues using two-photon excited fluorescence and second harmonic generation. Photomed. Laser Surg. 28(Suppl 1):S129–S133, 2010.
Ingman, W. V., J. Wyckoff, V. Gouon-Evans, J. Condeelis, and J. W. Pollard. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev. Dyn. 235:3222–3229, 2006.
Jung, J. C., and M. J. Schnitzer. Multiphoton endoscopy. Opt. Lett. 28:902–904, 2003.
Kaiser, W., and C. Garret. Two-photon excitation in CaF2: Eu2+. Phys. Rev. Lett. 7:229–231, 1961.
Kedrin, D., J. Wyckoff, E. Sahai, J. Condeelis, and J. E. Segall. Imaging tumor cell movement in vivo. Curr. Protoc. Cell Biol. Chapter 19:Unit 19.17, 2007.
Kim, K. H., C. Buehler, K. Bahlmann, T. Ragan, W. C. Lee, E. Nedivi, E. L. Heffer, S. Fantini, and P. T. So. Multifocal multiphoton microscopy based on multianode photomultiplier tubes. Opt. Express 15:11658–11678, 2007.
Kim, B. M., J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva. Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity. Lasers Surg. Med. 27:329–335, 2000.
Kim, P., M. Puoris’haag, D. Cote, C. P. Lin, and S. H. Yun. In vivo confocal and multiphoton microendoscopy. J. Biomed. Opt. 13:010501, 2008.
Kirkpatrick, N. D., M. A. Brewer, and U. Utzinger. Endogenous optical biomarkers of ovarian cancer evaluated with multiphoton microscopy. Cancer Epidemiol. Biomarkers Prev. 16:2048–2057, 2007.
Koehler, M. J., M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. Konig. Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases. Exp. Dermatol. 20:589–594, 2011.
Konig, K. Multiphoton microscopy in life sciences. J. Microsc. 200:83–104, 2000.
Konig, K., R. Buckle, M. Weinigel, P. Elsner, and M. Kaatz. Clinical multiphoton tomography and clinical two-photon microendoscopy. In: Multiphoton Microscopy in the Biomedical Sciences IX, Proceedings of the SPIE, Vol. 7183, edited by A. Periasamy and P. T. So, New York: Oxford University Press, 2009, pp. 7183191–7183199.
Konig, K., M. Speicher, R. Buckle, J. Reckfort, G. McKenzie, J. Welzel, M. J. Koehler, P. Elsner, and M. Kaatz. Clinical optical coherence tomography combined with multiphoton tomography of patients with skin diseases. J. Biophotonics 2:389–397, 2009.
Le Devedec, S. E., W. van Roosmalen, C. Pont, R. Lalai, H. de Bont, and B. van de Water. Two-photon intravital multicolour imaging to study metastatic behaviour of cancer cells in vivo. Methods Mol. Biol. 769:331–349, 2011.
Le Harzic, R., I. Riemann, M. Weinigel, K. Konig, and B. Messerschmidt. Rigid and high-numerical-aperture two-photon fluorescence endoscope. Appl. Opt. 48:3396–3400, 2009.
Lee, A. M. D., H. Wang, Y. Yu, S. Tang, J. Zhao, H. Lui, D. I. McLean, and H. Zeng. In vivo video rate multiphoton microscopy imaging of human skin. Opt. Lett. 36:2865–2867, 2011.
Lelek, M., E. Suran, F. Louradour, A. Barthelemy, B. Viellerobe, and F. Lacombe. Coherent femtosecond pulse shaping for the optimization of a non-linear micro-endoscope. Opt. Express 15:10154–10162, 2007.
Lin, H. J., P. Herman, and J. R. Lakowicz. Fluorescence lifetime-resolved pH imaging of living cells. Cytometry A: J. Int. Soc. Anal. Cytol. 52:77–89, 2003.
Lin, S. J., S. H. Jee, and C. Y. Dong. Multiphoton microscopy: a new paradigm in dermatological imaging. Eur. J. Dermatol. 17:361–366, 2007.
Llewellyn, M. E., R. P. Barretto, S. L. Delp, and M. J. Schnitzer. Minimally invasive high-speed imaging of sarcomere contractile dynamics in mice and humans. Nature 454:784–788, 2008.
Lohela, M., and Z. Werb. Intravital imaging of stromal cell dynamics in tumors. Curr. Opin. Genet. Dev. 20:72–78, 2010.
Lunt, S. J., C. Gray, C. C. Reyes-Aldasoro, S. J. Matcher, and G. M. Tozer. Application of intravital microscopy in studies of tumor microcirculation. J. Biomed. Opt. 15:011113, 2010.
Martini, J., V. Andresen, and D. Anselmetti. Scattering suppression and confocal detection in multifocal multiphoton microscopy. J. Biomed. Opt. 12:034010, 2007.
Masters, B., and P. So. Confocal microscopy and multi-photon excitation microscopy of human skin in vivo. Opt. Express 8:2–10, 2001.
Masters, B. R., P. T. So, C. Buehler, N. Barry, J. D. Sutin, W. W. Mantulin, and E. Gratton. Mitigating thermal mechanical damage potential during two-photon dermal imaging. J. Biomed. Opt. 9:1265–1270, 2004.
Matthews, T. E., I. R. Piletic, M. A. Selim, M. J. Simpson, and W. S. Warren. Pump-probe imaging differentiates melanoma from melanocytic nevi. Sci. Transl. Med. 3:71–72, 2011.
Matthews, T. E., J. W. Wilson, S. Degan, M. J. Simpson, J. Y. Jin, J. Y. Zhang, and W. S. Warren. In vivo and ex vivo epi-mode pump-probe imaging of melanin and microvasculature. Biomed Opt. Express 2:1576–1583, 2011.
Meek, K. M. The use of glutaraldehyde and tannic acid to preserve reconstituted collagen for electron microscopy. Histochemistry 73:115–120, 1981.
Meier, R., K. Kromer, H. Stepp, and R. Sroka. A comparison of confocal and two-photon microendoscopy. IFMBE Proc. 25(6):177–178, 2009.
Meyer, T., N. Bergner, C. Bielecki, C. Krafft, D. Akimov, B. F. Romeike, R. Reichart, R. Kalff, B. Dietzek, and J. Popp. Nonlinear microscopy, infrared, and Raman microspectroscopy for brain tumor analysis. J. Biomed. Opt. 16:021113, 2011.
Min, W., C. W. Freudiger, S. Lu, and X. S. Xie. Coherent nonlinear optical imaging: beyond fluorescence microscopy. Annu. Rev. Phys. Chem. 62:507–530, 2011.
Mohler, W., A. C. Millard, and P. J. Campagnola. Second harmonic generation imaging of endogenous structural proteins. Methods 29:97–109, 2003.
Nadiarnykh, O., R. B. LaComb, M. A. Brewer, and P. J. Campagnola. Alterations of the extracellular matrix in ovarian cancer studied by Second Harmonic Generation imaging microscopy. BMC Cancer 10:94, 2010.
Pantazis, P., J. Maloney, D. Wu, and S. E. Fraser. Second harmonic generating (SHG) nanoprobes for in vivo imaging. Proc. Natl Acad. Sci. USA 107:14535–14540, 2010.
Paoli, J., M. Smedh, and M. B. Ericson. Multiphoton laser scanning microscopy–a novel diagnostic method for superficial skin cancers. Semin. Cutan. Med. Surg. 28:190–195, 2009.
Paull, P. E., B. J. Hyatt, W. Wassef, and A. H. Fischer. Confocal laser endomicroscopy: a primer for pathologists. Arch. Pathol. Lab. Med. 135:1343–1348, 2011.
Pavlova, I., K. R. Hume, S. A. Yazinski, R. M. Peters, R. S. Weiss, and W. W. Webb. Multiphoton microscopy as a diagnostic imaging modality for lung cancer. Proc. Soc. Photo Opt. Instrum. Eng. 7569:756918, 2010.
Pawley, J. B. (ed.). Handbook of Biological Confocal Microscopy. New York: Springer, p. 1016, 2006.
Piletic, I. R., T. E. Matthews, and W. S. Warren. Probing near-infrared photorelaxation pathways in eumelanins and pheomelanins. J. Phys. Chem. A 114:11483–11491, 2010.
Piston, D. W., B. R. Masters, and W. W. Webb. Three-dimensionally resolved NAD(P)H cellular metabolic redox imaging of the in situ cornea with two-photon excitation laser scanning microscopy. J. Microsc. 178:20–27, 1995.
Provenzano, P. P., K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4:38, 2006.
Provenzano, P. P., K. W. Eliceiri, and P. J. Keely. Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment. Clin. Exp. Metastasis 26:357–370, 2009.
Provenzano, P. P., 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. 14:532–548, 2008.
Provenzano, P. P., D. R. Inman, K. W. Eliceiri, S. M. Trier, and P. J. Keely. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95:5374–5384, 2008.
Provenzano, P. P., C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri. Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer. J. Biomed. Opt. 13:031220, 2008.
Reeve, J. E., H. L. Anderson, and K. Clays. Dyes for biological second harmonic generation imaging. Phys. Chem. Chem. Phys. 12:13484–13498, 2010.
Rivera, D. R., C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu. Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue. Proc. Natl Acad. Sci. USA 108:17598–17603, 2011.
Roberts, M. S., Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. Konig, and W. Becker. Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy. Eur. J. Pharm. Biopharm. 77:469–488, 2011.
Rocheleau, J. V. and D. W. Piston. Two-photon excitation microscopy for the study of living cells and tissues. Curr. Protoc. Cell Biol. Chapter 4:Unit 4.11, 2003.
Rogart, J. N., J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson. Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo. Clin. Gastroenterol. Hepatol. 6:95–101, 2008.
Roth, S., and I. Freund. Second harmonic generation in collagen. J. Chem. Phys. 70:1637, 1979.
Schedin, P., and P. J. Keely. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb. Perspect. Biol. 3:a003228, 2011.
Skala, M. C., 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. USA 104:19494–19499, 2007.
Stoller, P., P. M. Celliers, K. M. Reiser, and A. M. Rubenchik. Quantitative second-harmonic generation microscopy in collagen. Appl. Opt. 42:5209–5219, 2003.
Straub, M., P. Lodemann, P. Holroyd, R. Jahn, and S. W. Hell. Live cell imaging by multifocal multiphoton microscopy. Eur. J. Cell Biol. 79:726–734, 2000.
Tewari, A. K., M. M. Shevchuk, J. Sterling, S. Grover, M. Herman, R. Yadav, K. Mudalair, A. Srivastava, M. A. Rubin, W. R. Zipfel, F. R. Maxfield, C. Xu, W. W. Webb, and S. Mukherjee. Multiphoton microscopy for structure identification in human prostate and periprostatic tissue: implications in prostate cancer surgery. BJU Int. 108(9):1421–1429, 2011.
Theodossiou, T., G. S. Rapti, V. Hovhannisyan, E. Georgiou, K. Politopoulos, and D. Yova. Thermally induced irreversible conformational changes in collagen probed by optical second harmonic generation and laser-induced fluorescence. Lasers Med. Sci. 17:34–41, 2002.
Tozer, G. M., S. M. Ameer-Beg, J. Baker, P. R. Barber, S. A. Hill, R. J. Hodgkiss, R. Locke, V. E. Prise, I. Wilson, and B. Vojnovic. Intravital imaging of tumour vascular networks using multi-photon fluorescence microscopy. Adv. Drug Deliv. Rev. 57:135–152, 2005.
Tsai, T. H., S. H. Jee, C. Y. Dong, and S. J. Lin. Multiphoton microscopy in dermatological imaging. J. Dermatol. Sci. 56:1–8, 2009.
van Munster, E. B., and T. W. Gadella. Fluorescence lifetime imaging microscopy (FLIM). Adv. Biochem. Eng. Biotechnol. 95:143–175, 2005.
Wang, B. G., K. Konig, and K. J. Halbhuber. Two-photon microscopy of deep intravital tissues and its merits in clinical research. J. Microsc. 238:1–20, 2010.
Wang, C. C., F. C. Li, R. J. Wu, V. A. Hovhannisyan, W. C. Lin, S. J. Lin, P. T. So, and C. Y. Dong. Differentiation of normal and cancerous lung tissues by multiphoton imaging. J. Biomed. Opt. 14:044034, 2009.
Wang, W., J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Huttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62:6278–6288, 2002.
Wang, W., J. B. Wyckoff, S. Goswami, Y. Wang, M. Sidani, J. E. Segall, and J. S. Condeelis. Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res. 67:3505–3511, 2007.
Wilder-Smith, P., T. Krasieva, W. G. Jung, J. Zhang, Z. Chen, K. Osann, and B. Tromberg. Noninvasive imaging of oral premalignancy and malignancy. J. Biomed. Opt. 10:051601, 2005.
Williams, R. M., A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel. Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy. Transl. Oncol. 3:181–194, 2010.
Williams, R. M., W. R. Zipfel, and W. W. Webb. Interpreting second-harmonic generation images of collagen I fibrils. Biophys. J. 88:1377–1386, 2005.
Wilson, J. W., T. E. Matthews, S. Degan, J. Y. Zhang, M. J. Simpson, and W. S. Warren. Pump-probe melanoma imaging: applications to high-resolution and in vivo microscopy. CLEO:2011—laser applications to photonic applications, OSA Technical Digest (CD) (Optical Society of America, 2011), paper PDPB5, 2011.
Wolf, K., S. Alexander, V. Schacht, L. M. Coussens, U. H. von Andrian, J. van Rheenen, E. Deryugina, and P. Friedl. Collagen-based cell migration models in vitro and in vivo. Semin. Cell Dev. Biol. 20:931–941, 2009.
Yan, J., G. Chen, J. Chen, N. Liu, S. Zhuo, H. Yu, and M. Ying. A pilot study of using multiphoton microscopy to diagnose gastric cancer. Surg. Endosc. 25:1425–1430, 2011.
Yan, L., C. T. Rueden, J. G. White, and K. W. Eliceiri. Applications of combined spectral lifetime microscopy for biology. Biotechniques 41:249, 251, 253 passim, 2006.
Zal, T., and G. Chodaczek. Intravital imaging of anti-tumor immune response and the tumor microenvironment. Semin. Immunopathol. 32:305–317, 2010.
Zhuo, S., J. Chen, S. Xie, Z. Hong, and X. Jiang. Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals. J. Biomed. Opt. 14:020503, 2009.
Zhuo, S., J. Yan, G. Chen, J. Chen, Y. Liu, J. Lu, X. Zhu, X. Jiang, and S. Xie. Label-free monitoring of colonic cancer progression using multiphoton microscopy. Biomed. Opt. Express 2:615–619, 2011.
Zipfel, W. R., 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. USA 100:7075–7080, 2003.
Zipfel, W. R., R. M. Williams, and W. W. Webb. Nonlinear magic: multiphoton microscopy in the biosciences. Nat. Biotechnol. 21:1369–1377, 2003.
Zoumi, A., A. Yeh, and B. J. Tromberg. Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence. Proc. Natl Acad. Sci. USA 99:11014–11019, 2002.
Acknowledgments
The authors thank the reviewers for their helpful suggestions on this manuscript, and sincerely apologize to all colleagues whose work we could not cite in this review due to space constraints. This work was supported by National Institute of Health grants R21DA030256 to SWP, and 1DP2OD006501-01 to EBB, and Department of Defense grant W81XWH-09-1-0405 to EBB. This paper is subject to the NIH Public Access Policy.
Disclosures
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Daniel Elson oversaw the review of this article.
Rights and permissions
About this article
Cite this article
Perry, S.W., Burke, R.M. & Brown, E.B. Two-Photon and Second Harmonic Microscopy in Clinical and Translational Cancer Research. Ann Biomed Eng 40, 277–291 (2012). https://doi.org/10.1007/s10439-012-0512-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-012-0512-9