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Profiling distinct mechanisms of tumour invasion for drug discovery: imaging adhesion, signalling and matrix turnover

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Abstract

Recent advances in microscopic imaging technology, fluorescent reporter reagents, 3-dimensional (3D) cell models and multiparametric image analysis have enhanced our ability to model and understand complex cell physiology. Extension of these approaches to live cell, kinetic studies allows further spatial and temporal understanding of a multitude of dynamic functional events, including tumour cell invasion. Recent in vivo and 3D in vitro studies reveal how tumour cells utilize a diverse variety of mechanisms to permit invasion through 3D tissue environments. Such high degrees of diversity and plasticity between invasion mechanisms present a significant challenge to the successful treatment of malignant cancer. This review examines how advances in time-resolved imaging has contributed to the characterization of distinct modes of invasion and their associated molecular mechanisms. Specifically, we highlight the development of fluorescent reporter molecules and their incorporation into more predictive 3D in vitro and in vivo models, to enhance mechanistic analysis of tumour invasion. We also highlight the latest advances in kinetic imaging instrumentation applicable to in vitro and in vivo models of tumour invasion. We discuss how multiparametric image analysis can be used to interpret image data generated by these approaches. We further discuss how these approaches can be integrated into drug discovery pipelines to facilitate evaluation and selection of candidate drugs and novel pharmaceutical compositions, targeting multiple invasive mechanisms.

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Abbreviations

3D:

3-dimensional

ECM:

Extracellular matrix

FAK:

Focal adhesion kinase

MMP:

Matrix metalloproteinase

GFP:

Green fluorescent protein

FRET:

Fluorescence resonance energy transfer

FLIM:

Fluorescence lifetime imaging

FRAP:

Fluorescence recovery after photobleaching

TCSPC:

Time correlated single photon counting

TIRF:

Total internal reflection fluorescence

ROS:

Reactive oxygen species

CALI:

Chromophore activated light inactivation

EMT:

Epithelial-mesenchymal-transition

MAT:

Mesenchymal-amoeboid-transition

ROCK:

Rho kinase

MRCK:

Myotonic dystrophy kinase-related Cdc42-binding kinase

References

  1. Price JT, Thompson EW (2002) Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets 6:217–233. doi:10.1517/14728222.6.2.217

    Article  PubMed  CAS  Google Scholar 

  2. Friedl P (2004) Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 16:14–23. doi:10.1016/j.ceb.2003.11.001

    Article  PubMed  CAS  Google Scholar 

  3. ParmoCabanas M, MolinaOrtiz I, MatiasRoman S et al (2006) Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes. J Pathol 208:108–118. doi:10.1002/path.1876

    Article  CAS  Google Scholar 

  4. Sahai E, Marshall CJ (2003) Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 5:711–719. doi:10.1038/ncb1019

    Article  PubMed  CAS  Google Scholar 

  5. Wolf K, Mazo I, Leung H et al (2003) Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 160:267–277. doi:10.1083/jcb.200209006

    Article  PubMed  CAS  Google Scholar 

  6. Lang P, Yeow K, Nichols A, Scheer A (2006) Cellular imaging in drug discovery. Nat Rev Drug Discov 5:343–356. doi:10.1038/nrd2008

    Article  PubMed  CAS  Google Scholar 

  7. Perlman ZE, Slack MD, Feng Y, Mitchison TJ, Wu LF, Altschuler SJ (2004) Multidimensional drug profiling by automated microscopy. Science 306:1194–1198. doi:10.1126/science.1100709

    Article  PubMed  CAS  Google Scholar 

  8. Tanaka M, Bateman R, Rauh D et al (2005) An unbiased cell morphology-based screen for new, biologically active small molecules. Plos Biol 3:e128. doi:10.1371/journal.pbio.0030128

    Article  PubMed  CAS  Google Scholar 

  9. Yarrow JC, Perlman ZE, Westwood NJ, Mitchison TJ (2004) A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods. BMC Biotechnol 4:21. doi:10.1186/1472-6750-4-21

    Article  PubMed  Google Scholar 

  10. Giepmans BN, Adams SR, Ellisman MH, Tsien RY (2006) The fluorescent toolbox for assessing protein location and function. Science 312:217–224. doi:10.1126/science.1124618

    Article  PubMed  CAS  Google Scholar 

  11. Pedelacq JD, Cabantous S, Tran T, Terwilliger TC, Waldo GS (2006) Engineering and characterization of a superfolder green fluorescent protein. Nat Biotechnol 24:79–88. doi:10.1038/nbt1172

    Article  PubMed  CAS  Google Scholar 

  12. Shaner NC, Steinbach PA, Tsien RY (2005) A guide to choosing fluorescent proteins. Nat Methods 2:905–909. doi:10.1038/nmeth819

    Article  PubMed  CAS  Google Scholar 

  13. Bruchez MP (2005) Turning all the lights on: quantum dots in cellular assays. Curr Opin Chem Biol 9:533–537. doi:10.1016/j.cbpa.2005.08.019

    Article  PubMed  CAS  Google Scholar 

  14. Gao X, Cui Y, Levenson RM, Chung LW, Nie S (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22:969–976. doi:10.1038/nbt994

    Article  PubMed  CAS  Google Scholar 

  15. Estrada CR, Salanga M, Bielenberg DR et al (2006) Behavioral profiling of human transitional cell carcinoma ex vivo. Cancer Res 66:3078–3086. doi:10.1158/0008-5472.CAN-05-3391

    Article  PubMed  CAS  Google Scholar 

  16. Gu W, Pellegrino T, Parak WJ et al (2007) Measuring cell motility using quantum dot probes. Methods Mol Biol 374:125–131

    PubMed  Google Scholar 

  17. Voura EB, Jaiswal JK, Mattoussi H, Simon SM (2004) Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nat Med 10:993–998. doi:10.1038/nm1096

    Article  PubMed  CAS  Google Scholar 

  18. Lukyanov KA, Chudakov DM, Lukyanov S, Verkhusha VV (2005) Innovation: Photoactivatable fluorescent proteins. Nat Rev Mol Cell Biol 6:885–991. doi:10.1038/nrm1741

    Article  PubMed  CAS  Google Scholar 

  19. Bulina ME, Chudakov DM, Britanova OV et al (2006) A genetically encoded photosensitizer. Nat Biotechnol 24:95–99. doi:10.1038/nbt1175

    Article  PubMed  CAS  Google Scholar 

  20. Jay DG, Sakurai T (1999) Chromophore-assisted laser inactivation (CALI) to elucidate cellular mechanisms of cancer. Biochim Biophys Acta 1424:M39–M48

    PubMed  CAS  Google Scholar 

  21. Tour O, Meijer RM, Zacharias DA, Adams SR, Tsien RY (2003) Genetically targeted chromophore-assisted light inactivation. Nat Biotechnol 21:1505–1508. doi:10.1038/nbt914

    Article  PubMed  CAS  Google Scholar 

  22. Clayton AH, Tavarnesi ML, Johns TG (2007) Unligated epidermal growth factor receptor forms higher order oligomers within microclusters on A431 cells that are sensitive to tyrosine kinase inhibitor binding. Biochemistry 46:4589–4597. doi:10.1021/bi700002b

    Article  PubMed  CAS  Google Scholar 

  23. Sato M, Ozawa T, Inukai K, Asano T, Umezawa Y (2002) Fluorescent indicators for imaging protein phosphorylation in single living cells. Nat Biotechnol 20:287–294. doi:10.1038/nbt0302-287

    Article  PubMed  CAS  Google Scholar 

  24. Ting AY, Kain KH, Klemke RL, Tsien RY (2001) Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells. Proc Natl Acad Sci USA 98:15003–15008. doi:10.1073/pnas.211564598

    Article  PubMed  CAS  Google Scholar 

  25. Vanderklish PW, Krushel LA, Holst BH, Gally JA, Crossin KL, Edelman GM (2000) Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc Natl Acad Sci USA 97:2253–2258. doi:10.1073/pnas.040565597

    Article  PubMed  CAS  Google Scholar 

  26. Grant DM, Elson DS, Schimpf D et al (2005) Optically sectioned fluorescence lifetime imaging using a Nipkow disk microscope and a tunable ultrafast continuum excitation source. Opt Lett 30:3353–3355. doi:10.1364/OL.30.003353

    Article  PubMed  CAS  Google Scholar 

  27. Uchimura T, Kawanabe S, Maeda Y, Imasaka T (2006) Fluorescence lifetime imaging microscope consisting of a compact picosecond dye laser and a gated charge-coupled device camera for applications to living cells. Anal Sci 22:1291–1295. doi:10.2116/analsci.22.1291

    Article  PubMed  CAS  Google Scholar 

  28. Carragher NO, Frame MC (2004) Focal adhesion and actin dynamics: a place where kinases and proteases meet to promote invasion. Trends Cell Biol 14:241–249. doi:10.1016/j.tcb.2004.03.011

    Article  PubMed  CAS  Google Scholar 

  29. Webb DJ, Brown CM, Horwitz AF (2003) Illuminating adhesion complexes in migrating cells: moving toward a bright future. Curr Opin Cell Biol 15:614–620. doi:10.1016/S0955-0674(03)00105-4

    Article  PubMed  CAS  Google Scholar 

  30. Miller WH, Keenan RM, Willette RN, Lark MW (2000) Identification and in vivo efficacy of small-molecule antagonists of integrin alphavbeta3 (the vitronectin receptor). Drug Discov Today 5:397–408. doi:10.1016/S1359-6446(00)01545-2

    Article  PubMed  CAS  Google Scholar 

  31. Ellerbroek SM, Fishman DA, Kearns AS, Bafetti LM, Stack MS (1999) Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin. Cancer Res 59:1635–1641

    PubMed  CAS  Google Scholar 

  32. Fishman DA, Kearns A, Chilukuri K et al (1998) Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen. Invasion Metastasis 18:15–26. doi:10.1159/000024495

    Article  PubMed  CAS  Google Scholar 

  33. Zutter MM, Santoro SA, Staatz WD, Tsung YL (1995) Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Proc Natl Acad Sci USA 92:7411–7415. doi:10.1073/pnas.92.16.7411

    Article  PubMed  CAS  Google Scholar 

  34. Plancon S, Morel-Kopp MC, Schaffner-Reckinger E, Chen P, Kieffer N (2001) Green fluorescent protein (GFP) tagged to the cytoplasmic tail of alphaIIb or beta3 allows the expression of a fully functional integrin alphaIIb(beta3): effect of beta3GFP on alphaIIb(beta3) ligand binding. Biochem J 357:529–536. doi:10.1042/0264-6021:3570529

    Article  PubMed  CAS  Google Scholar 

  35. Ballestrem C, Hinz B, Imhof BA, WehrleHaller B (2001) Marching at the front and dragging behind: differential alphaVbeta3-integrin turnover regulates focal adhesion behavior. J Cell Biol 155:1319–1332. doi:10.1083/jcb.200107107

    Article  PubMed  CAS  Google Scholar 

  36. Ramsay AG, Marshall JF, Hart IR (2007) Integrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev 26:567–578. doi:10.1007/s10555-007-9078-7

    Article  PubMed  CAS  Google Scholar 

  37. Caswell PT, Spence HJ, Parsons M et al (2007) Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments. Dev Cell 13:496–510. doi:10.1016/j.devcel.2007.08.012

    Article  PubMed  CAS  Google Scholar 

  38. Cai X, Lietha D, Ceccarelli DF et al (2008) Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol 28:201–214. doi:10.1128/MCB.01324-07

    Article  PubMed  CAS  Google Scholar 

  39. Wang Y, Chien S (2007) Analysis of integrin signaling by fluorescence resonance energy transfer. Methods Enzymol 426:177–201. doi:10.1016/S0076-6879(07)26009-4

    Article  PubMed  CAS  Google Scholar 

  40. Hegerfeldt Y, Tusch M, Brocker EB, Friedl P (2002) Collective cell movement in primary melanoma explants: plasticity of cell-cell interaction, beta1-integrin function, and migration strategies. Cancer Res 62:2125–2130

    PubMed  CAS  Google Scholar 

  41. von Wallbrunn A, Holtke C, Zuhlsdorf M, Heindel W, Schafers M, Bremer C (2007) In vivo imaging of integrin alpha v beta 3 expression using fluorescence-mediated tomography. Eur J Nucl Med Mol Imaging 34:745–754. doi:10.1007/s00259-006-0269-1

    Article  CAS  Google Scholar 

  42. Stehbens SJ, Paterson AD, Crampton MS et al (2006) Dynamic microtubules regulate the local concentration of E-cadherin at cell-cell contacts. J Cell Sci 119:1801–1811. doi:10.1242/jcs.02903

    Article  PubMed  CAS  Google Scholar 

  43. Zamir E, Geiger B (2001) Molecular complexity and dynamics of cell-matrix adhesions. J Cell Sci 114:3583–3590

    PubMed  CAS  Google Scholar 

  44. Miyamoto S, Akiyama SK, Yamada KM (1995) Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science 267:883–885. doi:10.1126/science.7846531

    Article  PubMed  CAS  Google Scholar 

  45. Webb DJ, Donais K, Whitmore LA et al (2004) FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat Cell Biol 6:154–161. doi:10.1038/ncb1094

    Article  PubMed  CAS  Google Scholar 

  46. ZaidelBar R, Ballestrem C, Kam Z, Geiger B (2003) Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J Cell Sci 116:4605–4613. doi:10.1242/jcs.00792

    Article  CAS  Google Scholar 

  47. Humphrey D, Rajfur Z, Vazquez ME et al (2005) In situ photoactivation of a caged phosphotyrosine peptide derived from focal adhesion kinase temporarily halts lamellar extension of single migrating tumor cells. J Biol Chem 280:22091–22101. doi:10.1074/jbc.M502726200

    Article  PubMed  CAS  Google Scholar 

  48. Rajfur Z, Roy P, Otey C, Romer L, Jacobson K (2002) Dissecting the link between stress fibres and focal adhesions by CALI with EGFP fusion proteins. Nat Cell Biol 4:286–293. doi:10.1038/ncb772

    Article  PubMed  CAS  Google Scholar 

  49. Choma DP, Milano V, Pumiglia KM, DiPersio CM (2007) Integrin alpha3beta1-dependent activation of FAK/Src regulates Rac1-mediated keratinocyte polarization on laminin-5. J Invest Dermatol 127:31–40. doi:10.1038/sj.jid.5700505

    Article  PubMed  CAS  Google Scholar 

  50. Carragher NO, Levkau B, Ross R, Raines EW (1999) Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. J Cell Biol 147:619–630. doi:10.1083/jcb.147.3.619

    Article  PubMed  CAS  Google Scholar 

  51. Cuevas BD, Abell AN, Witowsky JA et al (2003) MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. EMBO J 22:3346–3355. doi:10.1093/emboj/cdg322

    Article  PubMed  CAS  Google Scholar 

  52. Franco SJ, Rodgers MA, Perrin BJ et al (2004) Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat Cell Biol 6:977–983. doi:10.1038/ncb1175

    Article  PubMed  CAS  Google Scholar 

  53. Huttenlocher A, Palecek SP, Lu Q et al (1997) Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem 272:32719–32722. doi:10.1074/jbc.272.52.32719

    Article  PubMed  CAS  Google Scholar 

  54. Perrin BJ, Amann KJ, Huttenlocher A (2006) Proteolysis of cortactin by calpain regulates membrane protrusion during cell migration. Mol Biol Cell 17:239–250. doi:10.1091/mbc.E05-06-0488

    Article  PubMed  CAS  Google Scholar 

  55. Carragher NO, Fonseca BD, Frame MC (2004) Calpain activity is generally elevated during transformation but has oncogene-specific biological functions. Neoplasia 6:53–73

    PubMed  CAS  Google Scholar 

  56. Carragher NO, Walker SM, Scott Carragher LA et al (2006) Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: a link to integrin function. Oncogene 25:5726–5740. doi:10.1038/sj.onc.1209582

    Article  PubMed  CAS  Google Scholar 

  57. Ellis C, Moran M, McCormick F, Pawson T (1990) Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Nature 343:377–381. doi:10.1038/343377a0

    Article  PubMed  CAS  Google Scholar 

  58. Felsenfeld DP, Schwartzberg PL, Venegas A, Tse R, Sheetz MP (1999) Selective regulation of integrin–cytoskeleton interactions by the tyrosine kinase Src. Nat Cell Biol 1:200–206. doi:10.1038/12021

    Article  PubMed  CAS  Google Scholar 

  59. Frame MC, Fincham VJ, Carragher NO, Wyke JA (2002) v-Src’s hold over actin and cell adhesions. Nat Rev Mol Cell Biol 3:233–245. doi:10.1038/nrm779

    Article  PubMed  CAS  Google Scholar 

  60. Wu H, Reynolds AB, Kanner SB, Vines RR, Parsons JT (1991) Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol Cell Biol 11:5113–5124

    PubMed  CAS  Google Scholar 

  61. Brugnera E, Haney L, Grimsley C et al (2002) Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol 4:574–582

    PubMed  CAS  Google Scholar 

  62. Hildebrand JD, Taylor JM, Parsons JT (1996) An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase. Mol Cell Biol 16:3169–3178

    PubMed  CAS  Google Scholar 

  63. Zhai J, Lin H, Nie Z et al (2003) Direct interaction of focal adhesion kinase with p190RhoGEF. J Biol Chem 278:24865–24873. doi:10.1074/jbc.M302381200

    Article  PubMed  CAS  Google Scholar 

  64. Bretschneider T, Diez S, Anderson K et al (2004) Dynamic actin patterns and Arp2/3 assembly at the substrate-attached surface of motile cells. Curr Biol 14:1–10. doi:10.1016/j.cub.2003.12.005

    Article  PubMed  CAS  Google Scholar 

  65. Krylyshkina O, Anderson KI, Kaverina I et al (2003) Nanometer targeting of microtubules to focal adhesions. J Cell Biol 161:853–859. doi:10.1083/jcb.200301102

    Article  PubMed  CAS  Google Scholar 

  66. Manneville JB (2006) Use of TIRF microscopy to visualize actin and microtubules in migrating cells. Methods Enzymol 406:520–532. doi:10.1016/S0076-6879(06)06040-X

    Article  PubMed  CAS  Google Scholar 

  67. Cox EA, Huttenlocher A (1998) Regulation of integrin-mediated adhesion during cell migration. Microsc Res Tech 43:412–419. doi:10.1002/(SICI)1097-0029(19981201)43:5<412::AID-JEMT7>3.0.CO;2-F

    Article  PubMed  CAS  Google Scholar 

  68. Friedl P, Zanker KS, Brocker EB (1998) Cell migration strategies in 3-D extracellular matrix: differences in morphology, cell matrix interactions, and integrin function. Microsc Res Tech 43:369–378. doi:10.1002/(SICI)1097-0029(19981201)43:5<369::AID-JEMT3>3.0.CO;2-6

    Article  PubMed  CAS  Google Scholar 

  69. Petroll WM, Ma L (2003) Direct, dynamic assessment of cell-matrix interactions inside fibrillar collagen lattices. Cell Motil Cytoskeleton 55:254–264. doi:10.1002/cm.10126

    Article  PubMed  Google Scholar 

  70. Wolf K, Wu YI, Liu Y et al (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9:893–904. doi:10.1038/ncb1616

    Article  PubMed  CAS  Google Scholar 

  71. Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374. doi:10.1038/nrc1075

    Article  PubMed  CAS  Google Scholar 

  72. Bjorklund M, Koivunen E (2005) Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 1755:37–69

    PubMed  Google Scholar 

  73. Sanderson MP, Dempsey PJ, Dunbar AJ (2006) Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors. Growth Factors 24:121–136. doi:10.1080/08977190600634373

    Article  PubMed  CAS  Google Scholar 

  74. White JM (2003) ADAMs: modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol 15:598–606. doi:10.1016/j.ceb.2003.08.001

    Article  PubMed  CAS  Google Scholar 

  75. Giannelli G, FalkMarzillier J, Schiraldi O, StetlerStevenson WG, Quaranta V (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277:225–228. doi:10.1126/science.277.5323.225

    Article  PubMed  CAS  Google Scholar 

  76. Hooper S, Marshall JF, Sahai E (2006) Tumor cell migration in three dimensions. Methods Enzymol 406:625–643. doi:10.1016/S0076-6879(06)06049-6

    Article  PubMed  CAS  Google Scholar 

  77. Wyckoff JB, Pinner SE, Gschmeissner S, Condeelis JS, Sahai E (2006) ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr Biol 16:1515–1523. doi:10.1016/j.cub.2006.05.065

    Article  PubMed  CAS  Google Scholar 

  78. Condeelis J, Segall JE (2003) Intravital imaging of cell movement in tumours. Nat Rev Cancer 3:921–930. doi:10.1038/nrc1231

    Article  PubMed  CAS  Google Scholar 

  79. Xue C, Wyckoff J, Liang F et al (2006) Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis. Cancer Res 66:192–197. doi:10.1158/0008-5472.CAN-05-1242

    Article  PubMed  CAS  Google Scholar 

  80. Bremer C, Bredow S, Mahmood U, Weissleder R, Tung CH (2001) Optical imaging of matrix metalloproteinase-2 activity in tumors: feasibility study in a mouse model. Radiology 221:523–529. doi:10.1148/radiol.2212010368

    Article  PubMed  CAS  Google Scholar 

  81. Bremer C, Tung CH, Weissleder R (2002) Molecular imaging of MMP expression and therapeutic MMP inhibition. Acad Radiol 9(Suppl 2):S314–S315. doi:10.1016/S1076-6332(03)80214-3

    Article  PubMed  Google Scholar 

  82. Hsia DA, Mitra SK, Hauck CR et al (2003) Differential regulation of cell motility and invasion by FAK. J Cell Biol 160:753–767. doi:10.1083/jcb.200212114

    Article  PubMed  CAS  Google Scholar 

  83. Lampugnani MG (1999) Cell migration into a wounded area in vitro. Methods Mol Biol 96:177–182

    PubMed  CAS  Google Scholar 

  84. Chintala SK, Gokaslan ZL, Go Y, Sawaya R, Nicolson GL, Rao JS (1996) Role of extracellular matrix proteins in regulation of human glioma cell invasion in vitro. Clin Exp Metastasis 14:358–366. doi:10.1007/BF00123395

    Article  PubMed  CAS  Google Scholar 

  85. Nystrom ML, Thomas GJ, Stone M, Mackenzie IC, Hart IR, Marshall JF (2005) Development of a quantitative method to analyse tumour cell invasion in organotypic culture. J Pathol 205:468–475. doi:10.1002/path.1716

    Article  PubMed  CAS  Google Scholar 

  86. Hennigan RF, Hawker KL, Ozanne BW (1994) Fos-transformation activates genes associated with invasion. Oncogene 9:3591–3600

    PubMed  CAS  Google Scholar 

  87. Gaggioli C, Sahai E (2007) Melanoma invasion - current knowledge and future directions. Pigment Cell Res 20:161–172. doi:10.1111/j.1600-0749.2007.00378.x

    Article  PubMed  CAS  Google Scholar 

  88. Goswami S, Sahai E, Wyckoff JB et al (2005) Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 65:5278–5283. doi:10.1158/0008-5472.CAN-04-1853

    Article  PubMed  CAS  Google Scholar 

  89. Cornett DS, Reyzer ML, Chaurand P, Caprioli RM (2007) MALDI imaging mass spectrometry: molecular snapshots of biochemical systems. Nat Methods 4:828–833. doi:10.1038/nmeth1094

    Article  PubMed  CAS  Google Scholar 

  90. Rimsza LM, Leblanc ML, Unger JM et al (2008) Gene expression predicts overall survival in paraffin embedded tissues of diffuse large B cell lymphoma treated with R-CHOP. Blood 112:3425–3433

    Article  PubMed  CAS  Google Scholar 

  91. Zaman MH, Matsudaira P, Lauffenburger DA (2007) Understanding effects of matrix protease and matrix organization on directional persistence and translational speed in three-dimensional cell migration. Ann Biomed Eng 35:91–100. doi:10.1007/s10439-006-9205-6

    Article  PubMed  Google Scholar 

  92. Kharait S, Hautaniemi S, Wu S, Iwabu A, Lauffenburger DA, Wells A (2007) Decision tree modeling predicts effects of inhibiting contractility signaling on cell motility. BMC Syst Biol 1:9. doi:10.1186/1752-0509-1-9

    Article  PubMed  CAS  Google Scholar 

  93. Rauh A, Windischhofer W, Kovacevic A et al (2008) Endothelin (ET)-1 and ET-3 promote expression of c-fos and c-jun in human choriocarcinoma via ET(B) receptor-mediated G(i)- and G(q)-pathways and MAP kinase activation. Br J Pharmacol 154:13–24. doi:10.1038/bjp.2008.92

    Article  PubMed  CAS  Google Scholar 

  94. Rudin M, Weissleder R (2003) Molecular imaging in drug discovery and development. Nat Rev Drug Discov 2:123–131. doi:10.1038/nrd1007

    Article  PubMed  CAS  Google Scholar 

  95. Yamauchi K, Yang M, Jiang P et al (2006) Development of real-time subcellular dynamic multicolor imaging of cancer-cell trafficking in live mice with a variable-magnification whole-mouse imaging system. Cancer Res 66:4208–4214. doi:10.1158/0008-5472.CAN-05-3927

    Article  PubMed  CAS  Google Scholar 

  96. Bullen A (2008) Microscopic imaging techniques for drug discovery. Nat Rev Drug Discov 7:54–67. doi:10.1038/nrd2446

    Article  PubMed  CAS  Google Scholar 

  97. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737–749. doi:10.1038/nrc2229

    Article  PubMed  CAS  Google Scholar 

  98. Wang W, Goswami S, Sahai E, Wyckoff JB, Segall JE, Condeelis JS (2005) Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol 15:138–145. doi:10.1016/j.tcb.2005.01.003

    Article  PubMed  CAS  Google Scholar 

  99. Wyckoff JB, Wang Y, Lin EY et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656. doi:10.1158/0008-5472.CAN-06-1823

    Article  PubMed  CAS  Google Scholar 

  100. Bailly M, Yan L, Whitesides GM, Condeelis JS, Segall JE (1998) Regulation of protrusion shape and adhesion to the substratum during chemotactic responses of mammalian carcinoma cells. Exp Cell Res 241:285–299. doi:10.1006/excr.1998.4031

    Article  PubMed  CAS  Google Scholar 

  101. Alencar H, Mahmood U, Kawano Y, Hirata T, Weissleder R (2005) Novel multiwavelength microscopic scanner for mouse imaging. Neoplasia 7:977–983. doi:10.1593/neo.05376

    Article  PubMed  Google Scholar 

  102. Booth MJ (2007) Adaptive optics in microscopy. Philos Transact A Math Phys Eng Sci 365:2829–2843

    Article  PubMed  Google Scholar 

  103. Jung JC, Mehta AD, Aksay E, Stepnoski R, Schnitzer MJ (2004) In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy. J Neurophysiol 92:3121–3133. doi:10.1152/jn.00234.2004

    Article  PubMed  Google Scholar 

  104. Theer P, Hasan MT, Denk W (2003) Two-photon imaging to a depth of 1000 microm in living brains by use of a Ti:Al2O3 regenerative amplifier. Opt Lett 28:1022–1024. doi:10.1364/OL.28.001022

    Article  PubMed  CAS  Google Scholar 

  105. Cui JF, Liu YK, Zhang LJ et al (2006) Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro. Proteomics 6:5953–5961. doi:10.1002/pmic.200500460

    Article  PubMed  CAS  Google Scholar 

  106. Scott LA, Vass JK, Parkinson EK, Gillespie DA, Winnie JN, Ozanne BW (2004) Invasion of normal human fibroblasts induced by v-Fos is independent of proliferation, immortalization, and the tumor suppressors p16INK4a and p53. Mol Cell Biol 24:1540–1559. doi:10.1128/MCB.24.4.1540-1559.2004

    Article  PubMed  CAS  Google Scholar 

  107. Lidke DS, Lidke KA, Rieger B, Jovin TM, Arndt-Jovin DJ (2005) Reaching out for signals: filopodia sense EGF and respond by directed retrograde transport of activated receptors. J Cell Biol 170:619–626. doi:10.1083/jcb.200503140

    Article  PubMed  CAS  Google Scholar 

  108. Hamadi A, Bouali M, Dontenwill M, Stoeckel H, Takeda K, Ronde P (2005) Regulation of focal adhesion dynamics and disassembly by phosphorylation of FAK at tyrosine 397. J Cell Sci 118:4415–4425. doi:10.1242/jcs.02565

    Article  PubMed  CAS  Google Scholar 

  109. AdaNguema AS, Xenias H, Hofman JM, Wiggins CH, Sheetz MP, Keely PJ (2006) The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCepsilon. J Cell Sci 119:1307–1319. doi:10.1242/jcs.02835

    Article  CAS  Google Scholar 

  110. Baatz M, Arini N, Schape A, Binnig G, Linssen B (2006) Object-oriented image analysis for high content screening: detailed quantification of cells and sub cellular structures with the Cellenger software. Cytometry A 69:652–658. doi:10.1002/cyto.a.20289

    PubMed  Google Scholar 

  111. Murshid SA, Kamioka H, Ishihara Y, Ando R, Sugawara Y, TakanoYamamoto T (2007) Actin and microtubule cytoskeletons of the processes of 3D-cultured MC3T3–E1 cells and osteocytes. J Bone Miner Metab 25:151–158. doi:10.1007/s00774-006-0745-5

    Article  PubMed  CAS  Google Scholar 

  112. Michel R, Steinmeyer R, Falk M, Harms GS (2007) A new detection algorithm for image analysis of single, fluorescence-labeled proteins in living cells. Microsc Res Tech 70:763–770. doi:10.1002/jemt.20485

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

I would like to thank Andy Hargreaves, Director of the Advanced Science and Technology Lab, AstraZeneca and Margaret Frame, Assistant Director of the Beatson Institute for Cancer Research for their support in these studies and writing of this review article.

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  1. Advanced Science and Technology Laboratory, AstraZeneca Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK

    Neil O. Carragher

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Carragher, N.O. Profiling distinct mechanisms of tumour invasion for drug discovery: imaging adhesion, signalling and matrix turnover. Clin Exp Metastasis 26, 381–397 (2009). https://doi.org/10.1007/s10585-008-9222-y

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  • DOI: https://doi.org/10.1007/s10585-008-9222-y

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