Skip to main content
SpringerLink
Log in

In Vivo Imaging of Lymphatic Vessels and Lymph Nodes

  • Chapter
  • First Online:
Lymph Node Metastasis in Gastrointestinal Cancer

  • 897 Accesses

Abstract

Intravital (in vivo) imaging of lymphatic vessels and lymph node is clinically necessary during diagnosis or treatment of many conditions and diseases, including lymphedema and cancer metastasis. Cancers are complex diseases, and the cancer microenvironment, including lymphatic vessels and blood vessels, play important roles throughout cancer development, from carcinogenesis to malignancy. Efforts aimed at elucidating the pathology of complex cancers and developing novel therapeutic agents for cancer treatment are limited by the exclusive use of in vitro analysis of conventional cultured cells and tissue sections. Therefore, it is necessary to analyze cancer cells and their microenvironments spatiotemporally in vivo.

To address this issue, in vivo imaging has attracted attention in cancer research. Multiple in vivo imaging technologies have been developed, including computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI), and these modalities already serve as powerful tools for the diagnosis of cancer. Optical imaging in vivo using biological light has not yet been applied clinically so much; however, it has superior spatiotemporal resolution, making it possible to perform real-time observation of microscopic structures such as blood and lymphatic system in living animals. In this chapter, we first review technologies for visualizing the blood and lymphatic system for clinical applications, and then describe the use of in vivo imaging technology in experimental analysis of cancer cell growth, angiogenesis, lymphangiogenesis, and lymph node metastasis, focusing in particular on the usefulness of in vivo optical imaging technology.

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

Access this chapter

Log in via an institution
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
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

References

  1. Yoshimatsu Y, Miyazaki H, Watabe T. Roles of signaling and transcriptional networks in pathological lymphangiogenesis. Adv Drug Deliv Rev. 2016;99:161–71. https://doi.org/10.1016/j.addr.2016.01.020.

    Article  CAS  PubMed  Google Scholar 

  2. Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol. 2008;3:367–97.

    Article  CAS  Google Scholar 

  3. Rockson SG. Lymphatic investigation: from the endothelium to in vivo imaging. Lymphat Res Biol. 2003;1:99. https://doi.org/10.1089/153968503321642598.

    Article  PubMed  Google Scholar 

  4. Sevick-Muraca EM, Kwon S, Rasmussen JC. Emerging lymphatic imaging technologies for mouse and man. J Clin Invest. 2014;124:905–14. https://doi.org/10.1172/JCI71612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Munn LL, Padera TP. Imaging the lymphatic system. Microvasc Res. 2014;96:55–63. https://doi.org/10.1016/j.mvr.2014.06.006.

    Article  PubMed  Google Scholar 

  6. Kinmonth JB. Lymphangiography in man; a method of outlining lymphatic trunks at operation. Clin Sci (Lond). 1952;11:13–20.

    CAS  Google Scholar 

  7. Halsell JT, Smith JR, Bentlage CR, Park OK, Humphreys JW Jr. Lymphatic drainage of the breast demonstrated by vital dye staining and radiography. Ann Surg. 1965;162:221–6.

    Article  CAS  Google Scholar 

  8. Clement O, Luciani A. Imaging the lymphatic system: possibilities and clinical applications. Eur Radiol. 2004;14:1498–507.

    Article  Google Scholar 

  9. Weissleder R, Thrall JH. The lymphatic system: diagnostic imaging studies. Radiology. 1989;172:315–7.

    Article  CAS  Google Scholar 

  10. Wen Z, Tong G, Liu Y, Meeks JK, Ma D, Yang J. The lymphoscintigraphic manifestation of (99m)Tc-dextran lymphatic imaging in primary intestinal lymphangiectasia. Nucl Med Commun. 2014;35:493–500. https://doi.org/10.1097/MNM.0000000000000080.

    Article  CAS  PubMed  Google Scholar 

  11. Lu Q, Hua J, Kassir MM, Delproposto Z, Dai Y, Sun J, et al. Imaging lymphatic system in breast cancer patients with magnetic resonance lymphangiography. PLoS One. 2013;8:e69701. https://doi.org/10.1371/journal.pone.0069701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rane S, Donahue PM, Towse T, Ridner S, Chappell M, Jordi J, et al. Clinical feasibility of noninvasive visualization of lymphatic flow with principles of spin labeling MR imaging: implications for lymphedema assessment. Radiology. 2013;269:893–902. https://doi.org/10.1148/radiol.13120145.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Birim O, Kappetein AP, Stijnen T, Bogers AJ. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann Thorac Surg. 2005;79:375–82.

    Article  Google Scholar 

  14. Uchiyama S, Haruyama Y, Asada T, Hotokezaka M, Nagamachi S, Chijiiwa K. Role of the standardized uptake value of 18-fluorodeoxyglucose positron emission tomography-computed tomography in detecting the primary tumor and lymph node metastasis in colorectal cancers. Surg Today. 2012;42:956–61. https://doi.org/10.1007/s00595-012-0225-6.

    Article  PubMed  Google Scholar 

  15. Al-Sarraf N, Gately K, Lucey J, Wilson L, McGovern E, Young V. Lymph node staging by means of positron emission tomography is less accurate in non-small cell lung cancer patients with enlarged lymph nodes: analysis of 1,145 lymph nodes. Lung Cancer. 2008;60:62–8.

    Article  Google Scholar 

  16. Cooper KL, Harnan S, Meng Y, Ward SE, Fitzgerald P, Papaioannou D, et al. Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis. Eur J Surg Oncol. 2011;37:187–98. https://doi.org/10.1016/j.ejso.2011.01.003.

    Article  CAS  PubMed  Google Scholar 

  17. Akbulut Z, Canda AE, Atmaca AF, Caglayan A, Asil E, Balbay MD. Is positron emission tomography reliable to predict post-chemotherapy retroperitoneal lymph node involvement in advanced germ cell tumors of the testis? Urol J. 2011;8:120–6.

    PubMed  Google Scholar 

  18. Abe H, Schacht D, Kulkarni K, Shimauchi A, Yamaguchi K, Sennett CA, et al. Accuracy of axillary lymph node staging in breast cancer patients: an observer-performance study comparison of MRI and ultrasound. Acad Radiol. 2013;20:1399–404. https://doi.org/10.1016/j.acra.2013.08.003.

    Article  PubMed  Google Scholar 

  19. Rasmussen JC, Tan IC, Marshall MV, Fife CE, Sevick-Muraca EM. Lymphatic imaging in humans with near-infrared fluorescence. Curr Opin Biotechnol. 2009;20:74–82. https://doi.org/10.1016/j.copbio.2009.01.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mieog JS, Troyan SL, Hutteman M, Donohoe KJ, van der Vorst JR, Stockdale A, et al. Toward optimization of imaging system and lymphatic tracer for near-infrared fluorescent sentinel lymph node mapping in breast cancer. Ann Surg Oncol. 2011;18:2483–91. https://doi.org/10.1245/s10434-011-1566-x.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tan IC, Maus EA, Rasmussen JC, Marshall MV, Adams KE, Fife CE, et al. Assessment of lymphatic contractile function after manual lymphatic drainage using near-infrared fluorescence imaging. Arch Phys Med Rehabil. 2011;92:756–64. https://doi.org/10.1016/j.apmr.2010.12.027.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer. 2014;14:159–72. https://doi.org/10.1038/nrc3677.

    Article  CAS  PubMed  Google Scholar 

  23. Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17:545–80.

    Article  CAS  Google Scholar 

  24. Weissleder R, Pittet MJ. Imaging in the era of molecular oncology. Nature. 2008;452:580–9.

    Article  CAS  Google Scholar 

  25. Weissleder R, Nahrendorf M. Advancing biomedical imaging. Proc Natl Acad Sci U S A. 2015;112:14424–8.

    Article  CAS  Google Scholar 

  26. Luciani A, Itti E, Rahmouni A, Meignan M, Clement O. Lymph node imaging: basic principles. Eur J Radiol. 2006;58:338–44.

    Article  Google Scholar 

  27. Goh V, Padhani AR, Rasheed S. Functional imaging of colorectal cancer angiogenesis. Lancet Oncol. 2007;8:245–55.

    Article  Google Scholar 

  28. Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol. 2006;24:3293–8.

    Article  CAS  Google Scholar 

  29. Wells P, Jones T, Price P. Assessment of inter- and intrapatient variability in C15O2 positron emission tomography measurements of blood flow in patients with intra-abdominal cancer. Clin Cancer Res. 2003;9:6350–6.

    PubMed  Google Scholar 

  30. Cai W, Chwn X. Multimodality molecular imaging of tumor angiogenesis. J Nucl Med. 2008;49:113S–28S.

    Article  CAS  Google Scholar 

  31. Korpanty G, Carbon JG, Grayburn PA, Fleming JB, Brekken RA. Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature. Clin Cancer Res. 2007;13:323–30.

    Article  CAS  Google Scholar 

  32. Willimann JK, Paulmurugan R, Chen K, Gheysens O, Rodriguez-Porcel M, Lutz AM, et al. US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice. Radiology. 2008;246:508–18.

    Article  Google Scholar 

  33. Hara-Miyauchi C, Tsuji O, Hanyu A, Okada S, Yasuda A, Fukano T, et al. Bioluminescent system for dynamic imaging of cell and animal behavior. Biochem Biophys Res Commun. 2012;419:188–93.

    Article  CAS  Google Scholar 

  34. Katsuno Y, Hanyu A, Kanda H, Ishikawa Y, Akiyama F, Iwase T, et al. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene. 2008;27:6322–33.

    Article  CAS  Google Scholar 

  35. Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell. 2008;132:487–98. https://doi.org/10.1016/j.cell.2007.12.033.

    Article  CAS  PubMed  Google Scholar 

  36. Dan S, Okamura M, Mukai Y, Yoshimi H, Inoue Y, Hanyu A, et al. ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo. Eur J Cancer. 2012;48:936–43.

    Article  CAS  Google Scholar 

  37. Sugiyama M, Saitou T, Kurokawa H, Sakaue-Sawano A, Imamura T, Miyawaki A, et al. Live imaging-based model selection reveals periodic regulation of the stochastic G1/S phase transition in vertebrate axial development. PLoS Comput Biol. 2014;10:e1003957.

    Article  Google Scholar 

  38. Saitou T, Imamura T. Quantitative imaging with Fucci and mathematics to uncover temporal dynamics of cell cycle progression. Develop Growth Differ. 2016;58:6–15.

    Article  Google Scholar 

  39. Ogata F, Azuma R, Kikuchi M, Koshima I, Morimoto Y. Novel lymphography using indocyanine green dye for near-infrared fluorescence labeling. Ann Plast Surg. 2007;58:652–5.

    Article  CAS  Google Scholar 

  40. Kusano M, Tajima Y, Yamazaki K, Kato M, Watanabe M, Miwa M. Sentinel node mapping guided by indocyanine green fluorescence imaging: a new method for sentinel node navigation surgery in gastrointestinal cancer. Dig Surg. 2008;25:103–8. https://doi.org/10.1159/000121905.

    Article  PubMed  Google Scholar 

  41. Murawa D, Hirche C, Dresel S, Hünerbein M. Sentinel lymph node biopsy in breast cancer guided by indocyanine green fluorescence. Br J Surg. 2009;96:1289–94. https://doi.org/10.1002/bjs.6721.

    Article  CAS  PubMed  Google Scholar 

  42. Denk W, Strickler JH, Webb WW. Two-photon laser scanning fluorescence microscopy. Science. 1990;248:73–6.

    Article  CAS  Google Scholar 

  43. Helmchen F, Denk W. Deep tissue two-photon microscopy. Nat Methods. 2005;2:932–40.

    Article  CAS  Google Scholar 

  44. Theer P, Hasan MT, Denk W. Two-photon imaging to a depth of 1000 μm in living brains by use of a Ti:Al2O3 regenerative amplifier. Opt Lett. 2003;28:1022–4.

    Article  CAS  Google Scholar 

  45. Germain RN, Miller MJ, Dustin ML, Nussenzweig MC. Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol. 2006;6:497–507.

    Article  CAS  Google Scholar 

  46. Ishii M, Egen JG, Klauschen F, et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature. 2009;458:524–8.

    Article  CAS  Google Scholar 

  47. Miller MJ, Wei SH, Parker I, Cahalan MD. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science. 2002;296:1869–73.

    Article  CAS  Google Scholar 

  48. Stoll S, Delon J, Brotz TM, Germain RN. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science. 2002;296:1873–6.

    Article  Google Scholar 

  49. Bousso P, Bhakta NR, Lewis RS, Robey E. Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science. 2002;296:1876–80.

    Article  CAS  Google Scholar 

  50. Miller MJ, Wei SH, Cahalan MD, Parker I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc Natl Acad Sci U S A. 2003;100:2604–9.

    Article  CAS  Google Scholar 

  51. Mempel TR, Henrickson SE, Von Andrian UH. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature. 2004;427:154–9.

    Article  CAS  Google Scholar 

  52. Cahalan MD, Parker I, Wei SH, Miller MJ. Two-photon tissue imaging: seeing the immune system in a fresh light. Nat Rev Immunol. 2002;2:872–80.

    Article  CAS  Google Scholar 

  53. Bousso P, Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat Immunol. 2003;5:579–85.

    Article  Google Scholar 

  54. Miller MJ, Hejazi AS, Wei SH, Cahalan MD, Parker I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc Natl Acad Sci U S A. 2004;101:998–1003.

    Article  CAS  Google Scholar 

  55. Miller MJ, Safrina O, Parker I, Cahalan MD. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J Exp Med. 2004;200:847–56.

    Article  CAS  Google Scholar 

  56. Koga S, Oshima Y, Honkura N, Iimura T, Kameda K, Sato K, Yoshida M, et al. In vivo subcellular imaging of tumors in mouse models using a fluorophore-conjugated anti-carcinoembryonic antigen antibody in two-photon excitation microscopy. Cancer Sci. 2014;105:1299–306.

    Article  CAS  Google Scholar 

  57. Wang TD, Van Dam J. Optical biopsy: a new frontier in endoscopic detection and diagnosis. Clin Gastroenterol Hepatol. 2004;2:744–53.

    Article  Google Scholar 

  58. Huisken J, Swoger J, Del Bene F, Wittbrodt J, Stelzer EH. Optical sectioning deep inside live embryos by selective plane illumination microscopy. Science. 2004;305:1007–9.

    Article  CAS  Google Scholar 

  59. Maruyama A, Oshima Y, Kajiura-Kobayashi H, Nonaka S, Imamura T, Naruse K. Wide field intravital imaging by two-photon-excitation digital-scanned light-sheet microscopy (2p-DSLM) with a high-pulse energy laser. Biomed Opt Express. 2014;5:3311–25.

    Article  Google Scholar 

  60. Deguchi T, Fujimori KE, Kawasaki T, Maruyama K, Yuba S. In vivo visualization of the lymphatic vessels in pFLT4-EGFP transgenic medaka. Genesis. 2012;50:625–34.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

There are many important papers in this field; for reasons of space, we have not been able to mention all of them. We apologize to those investigators whose papers could not be cited.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Toon City, Japan

    Takeshi Imamura, Takashi Saitou, Sota Takanezawa & Ryosuke Kawakami

  2. Translational Research Center, Ehime University Hospital, Toon City, Japan

    Takeshi Imamura, Takashi Saitou, Sota Takanezawa & Ryosuke Kawakami

Authors
  1. Takeshi Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Saitou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sota Takanezawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryosuke Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeshi Imamura .

Editor information

Editors and Affiliations

  1. Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima, Japan

    Shoji Natsugoe

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Imamura, T., Saitou, T., Takanezawa, S., Kawakami, R. (2019). In Vivo Imaging of Lymphatic Vessels and Lymph Nodes. In: Natsugoe, S. (eds) Lymph Node Metastasis in Gastrointestinal Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-10-4699-5_7

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-4699-5_7

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-4698-8

  • Online ISBN: 978-981-10-4699-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation