Skip to main content

Intravital Microscopy for Molecular Imaging in Cancer Research

  • Chapter
  • First Online:
Advances in Intravital Microscopy
  • 877 Accesses

Abstract

Molecular imaging is an important tool in life sciences research and for clinical diagnosis and treatment. Among numerous imaging modalities, intravital microscopy (IVM) provides the best imaging spatial resolution in vivo and allows visualization of cellular and subcellular structures and functions. Because of its high resolution and the large number of available imaging agents, IVM has been used increasingly for the study of in vivo processes in many different fields. The application of IVM in cancer research and cancer treatment response assessment has been particularly fruitful. These IVM studies have disclosed that the cellular and subcellular dynamics during tumor progression and drug treatment in vivo are very different from those under in vitro conditions. Since the findings from IVM studies are obtained directly from intact living organisms, they may provide much more relevant information helpful to drug discovery and evaluation in clinics. In this chapter, we will briefly introduce the concepts of molecular imaging and the unique features of IVM. We will then highlight the most current IVM research in cancer biology and cancer drug response at the tissue, cellular and subcellular levels. We will end this chapter by outlining the future directions of IVM research.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

18F-FDG:

Fluorodeoxyglucose

CARS:

Coherent anti-stokes raman scattering

CCL1:

Chemokine (C-C motif) ligand 1

CT:

Computed tomography

DEVD:

Aspartic acid-glutamic acid-valine-aspartic acid

ECM:

Extracellular matrix

FAD:

Flavin adenine dinucleotide

FCS:

Fluorescence Correlation Spectroscopy

FLIM:

Fluorescence-lifetime imaging microscopy

FRAP:

Fluorescence recovery after photobleaching

FRET:

Förster resonance energy transfer

GFP:

Green fluorescent protein

IR/NIR:

Infrared/ Near-infrared

IVM:

Intravital microscopy

mKO2:

Monomeric Kusabira-Orange 2

MMP:

Metalloproteinase

MRI:

Magnetic resonance imaging

NADH:

Nicotinamide adenine dinucleotide

OFDI:

Optical frequency domain imaging

PARP-1:

Poly(ADP-ribose) polymerase-1

PARPi:

Poly(ADP-ribose) polymerase-1 inhibitor

PET:

Positron emission tomography

RFP:

Red fluorescent protein

ROCK:

Rho-associated protein kinase

scVEGF:

Single-chain vascular endothelial growth factor

SERS:

Surface enhanced Raman scattering

SHG:

Second harmonic generation

SNR:

Signal-to-noise ratio

SPECT:

Single-photon emission computed tomography

TGF-β:

Transforming growth factor beta

VEGF:

Vascular endothelial growth factor

YFP:

Yellow fluorescent protein

References

  • Alexandrakis G, Brown EB, Tong RT et al (2004) Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors. Nat Med 10:203–207

    Article  CAS  PubMed  Google Scholar 

  • Al-Rawi AAM, Jiang WG (2011) Lymphangiogenesis and cancer metastasis. J Cell Mol Med 16:1405–1416

    Google Scholar 

  • Amornphimoltham P, Masedunskas A, Weigert R (2010) Intravital microscopy as a tool to study drug delivery in preclinical studies. Adv Drug Deliv Rev 63:119–128

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Apte S, Chin FT, Graves EE et al (2011) Molecular imaging of hypoxia: strategies for probe design and application. Curr Org Synth 8:593–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Backer MV, Levashova Z, Patel V et al (2007) Molecular imaging of VEGF receptors in angiogenic vasculature with single-chain VEGF-based probes. Nat Med 13:504–509

    Article  CAS  PubMed  Google Scholar 

  • Bajénoff M, Breart B, Huang AYC et al (2006) Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. J Exp Med 203:619–631

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bao B, Groves K, Zhang J et al (2012) In vivo imaging and quantification of carbonic anhydrase IX expression as an endogenous biomarker of tumor hypoxia. PLoS One 7:e50860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Beerling E, Ritsma L, Vrisekoop N et al (2011) Intravital microscopy: new insights into metastasis of tumors. J Cell Sci 124:299–310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bhang SH, Won N, Lee T-J et al (2009) Hyaluronic acid-quantum dot conjugates for in vivo lymphatic vessel imaging. ACS Nano 3:1389–1398

    Article  CAS  PubMed  Google Scholar 

  • Bhirde AA, Patel V, Gavard J et al (2009) Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. ACS Nano 3:307–316

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Blum G, Mullins SR, Keren K et al (2005) Dynamic imaging of protease activity with fluorescently quenched activity-based probes. Nat Chem Biol 1:203–209

    Article  CAS  PubMed  Google Scholar 

  • Boissonnas A, Fetler L, Zeelenberg IS et al (2007) In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med 204:345–356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Breart B, Lemaître F, Celli S, Bousso P (2008) Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest 118:1390–1397

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brown EB, Campbell RB, Tsuzuki Y et al (2001) In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat Med 7:864–868

    Article  CAS  PubMed  Google Scholar 

  • Brown E, Munn LL, Fukumura D, Jain RK (2010) In vivo imaging of tumors. Cold Spring Harbor Protoc. 2010:pdb.prot5452, Vol 7

    Google Scholar 

  • Cao Y-A, Wagers AJ, Beilhack A et al (2004) Shifting foci of hematopoiesis during reconstitution from single stem cells. Proc Natl Acad Sci U S A 101:221–226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen J, Li Y, Yu T-S et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:1–6

    Google Scholar 

  • Cherry SR (2006) Multimodality in vivo imaging systems: twice the power or double the trouble? Annu Rev Biomed Eng 8:35–62

    Article  CAS  PubMed  Google Scholar 

  • Condeelis J, Segall J (2003) Intravital imaging of cell movement in tumours. Nat Rev Cancer 3:921–930

    Article  CAS  PubMed  Google Scholar 

  • Conley SJ, Gheordunescu E, Kakarala P et al (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109:2784–2789

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Coppieters K, Martinic MM, Kiosses WB et al (2010) A novel technique for the in vivo imaging of autoimmune diabetes development in the pancreas by two-photon microscopy. PLoS One 5:e15732

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Culver J, Akers W, Achilefu S (2008) Multimodality molecular imaging with combined optical and SPECT/PET modalities. J Nucl Med 49:169–172

    Article  PubMed  Google Scholar 

  • Dellian M, Helmlinger G, Yuan F, Jain RK (1996) Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients. Br J Cancer 74:1206–1215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Driessens G, Beck B, Caauwe A et al (2012) Defining the mode of tumour growth by clonal analysis. Nature 488:1–5

    Article  CAS  Google Scholar 

  • Egeblad M, Ewald AJ, Askautrud HA et al (2008) Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis Model Mech 1:155–167

    Article  PubMed Central  PubMed  Google Scholar 

  • Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18:884–901

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Eikenes L, Tari M, Tufto I et al (2005) Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer 93:81–88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Elstrom RL, Bauer DE, Buzzai M et al (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899

    Article  CAS  PubMed  Google Scholar 

  • Erikson A, Tufto I, Bjønnum AB et al (2008) The impact of enzymatic degradation on the uptake of differently sized therapeutic molecules. Anticancer Res 28:3557–3566

    PubMed  Google Scholar 

  • Escobedo JO, Rusin O, Lim S, Strongin RM (2010) NIR dyes for bio imaging applications. Curr Opin Chem Biol 14:64–70

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Estrella V, Chen T, Lloyd M et al (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73:1524–1535

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Filonov GS, Piatkevich KD, Ting L-M et al (2011) Bright and stable near-infrared fluorescent protein for in vivo imaging. Nat Biotechnol 29:757–761

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Folgueras AR, Pendás AM, Sánchez LM, López-Otín C (2004) Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 48:411–424

    Article  CAS  PubMed  Google Scholar 

  • Foudi A, Hochedlinger K, Van Buren D et al (2009) Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat Biotechnol 27:84–90

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frantz C, Stewart KM, Weaver VM (2010) The extracellular matrix at a glance. J Cell Sci 123:4195–4200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Friedl P, Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147:992–1009

    Article  CAS  PubMed  Google Scholar 

  • Fukumura D, Xu L, Chen Y et al (2001) Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61:6020–6024

    CAS  PubMed  Google Scholar 

  • Fukumura D, Duda DG, Munn LL, Jain RK (2010) Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation 17:206–225

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gambhir SS (2013) Molecular imaging primer, 1st edn. Available at the Apple bookstore for iPAD or Mac)

    Google Scholar 

  • Gaustad J-V, Simonsen TG, Leinaas MN, Rofstad EK (2012) Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts. BMC Cancer 12:388

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Germano G, Frapolli R, Belgiovine C et al (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23:249–262

    Article  CAS  PubMed  Google Scholar 

  • Giampieri S, Manning C, Hooper S et al (2009) Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 11:1287–1296

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Goel S, Wong AH-K, Jain RK (2012) Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med 2:a006486

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Grinvald A, Shoham D, Shmuel A et al (1991) In-vivo optical imaging of cortical architecture and dynamics. Brain 34:1–91

    Google Scholar 

  • Hadjantonakis A-K, Papaioannou VE (2004) Dynamic in vivo imaging and cell tracking using a histone fluorescent protein fusion in mice. BMC Biotechnol 4:33

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Han J, Burgess K (2010) Fluorescent indicators for intracellular pH. Chem Rev 110:2709–2728

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Harris AL (2002) Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  CAS  PubMed  Google Scholar 

  • Helmlinger G, Yuan F, Dellian M, Jain RK (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3:177–182

    Article  CAS  PubMed  Google Scholar 

  • Hoshida T, Isaka N, Hagendoorn J et al (2006) Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 66:8065–8075

    Article  CAS  PubMed  Google Scholar 

  • Hulit J, Kedrin D, Gligorijevic B et al (2012) The use of fluorescent proteins for intravital imaging of cancer cell invasion. Methods Mol Biol 872:15–30

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Humphries A, Cereser B, Gay LJ et al (2013) Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution. Proc Natl Acad Sci U S A 110:E2490–E2499

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Imanishi Y, Batten ML, Piston DW et al (2004) Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J Cell Biol 164:373–383

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Isaka N, Padera TP, Hagendoorn J et al (2004) Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res 64:4400–4404

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Smith BR, Parashurama N et al (2012) Unexpected dissemination patterns in lymphoma progression revealed by serial imaging within a murine lymph node. Cancer Res 72:6111–6118

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jain RK, Munn LL, Fukumura D (2011) Tumor models in cancer research. In: Teicher BA (ed) Cancer drug discovery and development. Springer, New York; pp 641–679

    Google Scholar 

  • James ML, Gambhir SS (2012) A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 92:897–965

    Article  CAS  PubMed  Google Scholar 

  • Janssen A, Beerling E, Medema R, van Rheenen J (2013) Intravital FRET imaging of tumor cell viability and mitosis during chemotherapy. PLoS One 8:e64029

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kardash E, Reichman-Fried M, Maître J-L et al (2010) A role for Rho GTPases and cell-cell adhesion in single-cell motility in vivo. Nat Cell Biol 12:47–53

    Article  CAS  PubMed  Google Scholar 

  • Kedrin D, Gligorijevic B, Wyckoff J et al (2008) Intravital imaging of metastatic behavior through a mammary imaging window. Nat Methods 5:1019–1021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Keese M, Yagublu V, Schwenke K et al (2010) Fluorescence lifetime imaging microscopy of chemotherapy-induced apoptosis resistance in a syngenic mouse tumor model. Int J Cancer 126:104–113

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi H, Choyke PL (2011) Target-cancer-cell-specific activatable fluorescence imaging probes: rational design and in vivo applications. Acc Chem Res 44:83–90

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    Article  CAS  PubMed  Google Scholar 

  • Kossodo S, Pickarski M, Lin S-A et al (2010) Dual in vivo quantification of integrin-targeted and protease-activated agents in cancer using fluorescence molecular tomography (FMT). Mol Imaging Biol 12:488–499

    Article  PubMed  Google Scholar 

  • Kotsuma M, Parashurama N, Smith BR et al (2012) Nondestructive, serial in vivo imaging of a tissue-flap using a tissue adhesion barrier Applications for IVM imaging in the mammary fat pad and lymph node. Intr Vital 1:69–76

    Google Scholar 

  • Kuchimaru T, Kadonosono T, Tanaka S et al (2010) In vivo imaging of HIF-active tumors by an oxygen-dependent degradation protein probe with an interchangeable labeling system. PLoS One 5:e15736

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee S, Ryu JH, Park K et al (2009) Polymeric nanoparticle-based activatable near-infrared nanosensor for protease determination in vivo. Nano Lett 9:4412–4416

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee S, Vinegoni C, Feruglio PF et al (2012) Real-time in vivo imaging of the beating mouse heart at microscopic resolution. Nat Commun 3:1054

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Lehr HA, Leunig M, Menger MD et al (1993) Dorsal skinfold chamber technique for intravital microscopy in nude mice. Am J Pathol 143:1055–1062

    CAS  PubMed Central  PubMed  Google Scholar 

  • Leu AJ, Berk DA, Lymboussaki A et al (2000) Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60:4324–4327

    CAS  PubMed  Google Scholar 

  • Levental KR, Yu H, Kass L et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li Z, Wilson KD, Smith B et al (2009) Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. PLoS One 4:13

    Google Scholar 

  • Liu J, Liao S, Diop-Frimpong B et al (2012) TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci 109:16618–16623

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Livet J, Weissman TA, Kang H et al (2007) Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450:56–62

    Article  CAS  PubMed  Google Scholar 

  • Looney MR, Thornton EE, Sen D et al (2011) Stabilized imaging of immune surveillance in the mouse lung. Nat Methods 8:91–96

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21:283–296

    Article  CAS  PubMed  Google Scholar 

  • Magzoub M, Jin S, Verkman AS (2008) Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. FASEB J 22:276–284

    Article  CAS  PubMed  Google Scholar 

  • Mahmood U, Weissleder R (2003) Near-infrared optical imaging of proteases in cancer. Mol Cancer Ther 2:489–496

    CAS  PubMed  Google Scholar 

  • Manning CS, Jenkins R, Hooper S et al (2013) Intravital imaging reveals conversion between distinct tumor vascular morphologies and localized vascular response to Sunitinib. Intra Vital 2:1–12

    Google Scholar 

  • Martin GR, Jain RK (1994) Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res 54:5670–5674

    CAS  PubMed  Google Scholar 

  • Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12:323–334

    Article  CAS  PubMed  Google Scholar 

  • Matise LA, Palmer TD, Ashby WJ et al (2012) Lack of transforming growth factor-beta signaling promotes collective cancer cell invasion through tumor-stromal crosstalk. Breast Cancer Res 14:R98

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McGhee EJ, Morton JP, Von Kriegsheim A et al (2011) FLIM-FRET imaging in vivo reveals 3D-environment spatially regulates RhoGTPase activity during cancer cell invasion. Small GTPases 2:239–244

    Article  PubMed Central  PubMed  Google Scholar 

  • McMillin DW, Negri JM, Mitsiades CS (2013) The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 12:217–228

    Article  CAS  PubMed  Google Scholar 

  • Meulmeester E, Ten Dijke P (2011) The dynamic roles of TGF-β in cancer. J Pathol 223:205–218

    Article  CAS  PubMed  Google Scholar 

  • Mikhail AS, Allen C (2010) Block copolymer micelles for delivery of cancer therapy: transport at the whole body, tissue and cellular levels. J Control Release 138:214–223

    Article  CAS  Google Scholar 

  • Mrass P, Kinjyo I, Ng LG et al (2008) CD44 mediates successful interstitial navigation by killer T cells and enables efficient antitumor immunity. Immunity 29:971–985

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mueller MM, Fusenig NE (2004) Friends or foes – bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849

    Article  CAS  PubMed  Google Scholar 

  • Nakasone ES, Askautrud HA, Kees T et al (2012) Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21:488–503

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nobis M, McGhee EJ, Morton JP et al (2013) Intravital FLIM-FRET imaging reveals dasatinibinduced spatial control of Src in pancreatic cancer. Cancer Res 73:4674–4686

    Article  CAS  PubMed  Google Scholar 

  • Olson MF, Sahai E (2009) The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis 26:273–287

    Article  PubMed  Google Scholar 

  • Orth JD, Kohler RH, Foijer F et al (2011) Analysis of mitosis and antimitotic drug responses in tumors by in vivo microscopy and single-cell pharmacodynamics. Cancer Res 71:4608–4616

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Padera TP, Kadambi A, Di Tomaso E et al (2002) Lymphatic metastasis in the absence of functional intra tumor lymphatics. Science 296:1883–1886

    Article  CAS  PubMed  Google Scholar 

  • Palmer GM, Fontanella AN, Shan S et al (2011) In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters. Nat Protoc 6:1355–1366

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Parks SK, Mazure NM, Counillon L, Pouysségur J (2013) Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels. J Cell Physiol 228:1854–1862

    Article  CAS  PubMed  Google Scholar 

  • Perentes JY, Mckee TD, Ley CD et al (2009) In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts. Nat Methods 6:2008–2010

    Article  CAS  Google Scholar 

  • Philippar U, Roussos ET, Oser M et al (2008) A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev Cell 15:813–828

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316:1324–1331

    Article  CAS  PubMed  Google Scholar 

  • Pink DBS, Schulte W, Parseghian MH et al (2012) Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery. PLoS One 7:e33760

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pinto MR, Schanze KS (2004) Amplified fluorescence sensing of protease activity with conjugated polyelectrolytes. Proc Natl Acad Sci U S A 101:7505–7510

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Provenzano PP, Eliceiri KW, Campbell JM et al (2006) Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 4:38

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW et al (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Provenzano PP, Eliceiri KW, Keely PJ (2009) Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment. Clin Exp Metastasis 26:357–370

    Article  CAS  PubMed  Google Scholar 

  • Provenzano P, Cuevas C, Chang A et al (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9:378–390

    Article  CAS  PubMed  Google Scholar 

  • Ray P, De A, Min J-J et al (2004) Imaging tri-fusion multimodality reporter gene expression in living subjects. Cancer Res 64:1323–1330

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ritsma L, Steller EJA, Ellenbroek SIJ et al (2013) Surgical implantation of an abdominal imaging window for intravital microscopy. Nat Protoc 8:583–594

    Article  CAS  PubMed  Google Scholar 

  • Sakaue-Sawano A, Ohtawa K, Hama H et al (2008) Tracing the silhouette of individual cells in S/G2/M phases with fluorescence. Chem Biol 15:1243–1248

    Article  CAS  PubMed  Google Scholar 

  • Salnikov AV, Roswall P, Sundberg C et al (2005) Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma. Lab Invest 85:512–521

    Article  CAS  PubMed  Google Scholar 

  • Sanz-Moreno V, Gadea G, Ahn J et al (2008) Rac activation and inactivation control plasticity of tumor cell movement. Cell 135:510–523

    Article  CAS  PubMed  Google Scholar 

  • Schepers AG, Snippert HJ, Stange DE et al (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 730:730–735

    Article  CAS  Google Scholar 

  • Serrels A, Timpson P, Canel M et al (2009) Real-time study of E-Cadherin and membrane dynamics in living animals: implications for disease modeling and drug development. Cancer Res 69:2714–2719

    Article  CAS  PubMed  Google Scholar 

  • Shen B, Jeon J, Palner M et al (2013) Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-triggered nanoaggregation probe. Angewandte Chemie 52:10511–10514

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shojaei F, Wu X, Malik AK et al (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1+ myeloid cells. Nat Biotechnol 25:911–920

    Article  CAS  PubMed  Google Scholar 

  • Skala MC, Riching KM, Gendron-Fitzpatrick A et al (2007) 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 104:19494–19499

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith ML, Gourdon D, Little WC et al (2007) Force-induced unfolding of fibronectin in the extracellular matrix of living cells. PLoS Biol 5:12

    Article  CAS  Google Scholar 

  • Smith BR, Cheng Z, De A et al (2008) Real-time intravital imaging of RGD-quantum dot binding to luminal endothelium in mouse tumor neovasculature. Nano Lett 8:2599–2606

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith BR, Cheng Z, De A et al (2010) Dynamic visualization of RGD-quantum dot binding to tumor neovasculature and extravasation in multiple living mouse models using intravital microscopy. Small 6:2222–2229

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith BR, Zavaleta C, Rosenberg J et al (2013) High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model. Nano Today 8:126–137

    Article  CAS  Google Scholar 

  • Snoeks TJA, Löwik CWGM, Kaijzel EL (2010) ‘In vivo’ optical approaches to angiogenesis imaging. Angiogenesis 13:135–147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Steven P, Bock F, Hüttmann G, Cursiefen C (2011) Intravital two-photon microscopy of immune cell dynamics in corneal lymphatic vessels. PLoS One 6:e26253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stoll S, Delon J, Brotz TM, Germain RN (2002) Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296:1873–1876

    Article  PubMed  Google Scholar 

  • Tada H, Higuchi H, Wanatabe TM, Ohuchi N (2007) In vivo real-time tracking of single quantum dots conjugated with monoclonal anti-HER2 antibody in tumors of mice. Cancer Res 67:1138–1144

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Morimoto Y, Toiyama Y et al (2012) In vivo time-course imaging of tumor angiogenesis in colorectal liver metastases in the same living mice using two-photon laser scanning microscopy. J Oncol 2012:265487

    Article  PubMed Central  PubMed  Google Scholar 

  • Thurber G, Yang K, Reiner T et al (2013) Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat Commun 4:1505

    Article  CAS  Google Scholar 

  • Timpson P, McGhee EJ, Morton JP et al (2011) Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53. Cancer Res 71:747–757

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150

    Article  CAS  PubMed  Google Scholar 

  • Trédan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454

    Article  PubMed  CAS  Google Scholar 

  • Tsai YC, Mendoza A, Mariano JM et al (2007) The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat Med 13:1504–1509

    Article  CAS  PubMed  Google Scholar 

  • Tsourkas A, Shinde-Patil VR, Kelly KA et al (2005) In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. Bioconjug Chem 16:576–581

    Article  CAS  PubMed  Google Scholar 

  • Tufto I, Hansen R, Byberg D et al (2007) The effect of collagenase and hyaluronidase on transient perfusion in human osteosarcoma xenografts grown orthotopically and in dorsal skinfold chambers. Anticancer Res 27:1475–1481

    CAS  PubMed  Google Scholar 

  • Vakoc BJ, Lanning RM, Tyrrell JA et al (2009) Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat Med 15:1219–1223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Weissleder R, Ntziachristos V (2003) Shedding light onto live molecular targets. Nat Med 9:123–128

    Article  CAS  PubMed  Google Scholar 

  • Williams RM, Zipfel WR, Webb WW (2005) Interpreting second-harmonic generation images of collagen I fibrils. Biophys J 88:1377–1386

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    Article  CAS  PubMed  Google Scholar 

  • Wilson A, Laurenti E, Oser G et al (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135:1118–1129

    Article  CAS  PubMed  Google Scholar 

  • Wyckoff JB, Pinner SE, Gschmeissner S et al (2006) ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr Biol 16:1515–1523

    Article  CAS  PubMed  Google Scholar 

  • Xia Z, Xing Y, Jeon J et al (2011) Immobilizing reporters for molecular imaging of the extracellular microenvironment in living animals. ACS Chem Biol 6:1117–1126

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yamamoto N, Jiang P, Yang M et al (2004) Cellular dynamics visualized in live cells in vitro and in vivo by differential dual-color nuclear-cytoplasmic fluorescent-protein expression. Cancer Res 64:4251–4256

    Article  CAS  PubMed  Google Scholar 

  • Yan X, Ray P, Paulmurugan R et al (2013) A transgenic tri-modality reporter mouse. PLoS One 8:e73580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yu H, Mouw JK, Weaver VM (2011) Forcing form and function: biomechanical regulation of tumor evolution. Trends Cell Biol 21:47–56

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhu L, Xie J, Swierczewska M et al (2011) Dual-functional, receptor-targeted fluorogenic probe for in vivo imaging of extracellular protease expressions. Bioconjug Chem 22:1001–1005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sanjiv Sam Gambhir .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Yu, H., Gambhir, S.S. (2014). Intravital Microscopy for Molecular Imaging in Cancer Research. In: Weigert, R. (eds) Advances in Intravital Microscopy. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9361-2_12

Download citation

Publish with us

Policies and ethics