The Role of Lymphatics in Cancer as Assessed by Near-Infrared Fluorescence Imaging
- 324 Downloads
The lymphatic system is the secondary circulatory system responsible for fluid homeostasis and protein transport in the body. In addition, because the lymphatic system provides a primary pathway for cancer metastasis, lymph node involvement is routinely used as a determinant in cancer staging. Despite their importance, the lymphatics remain poorly understood, in part because of the historic lack of imaging modalities with sufficient spatial and/or temporal resolution to visualize the fine lymphatic structure and subtle contractile function. In recent years, near-infrared fluorescence (NIRF) imaging has emerged as a new imaging modality to non-invasively visualize the lymphatics and assess contractile lymphatic function in humans following administration of microdose amounts of a NIRF contrast agent. In this contribution, we first review NIRF imaging and its clinical application in sentinel lymph node mapping, intraoperative guidance, and assessing the architecture and contractile function of the lymphatics in health and in cancer-related lymphedema. We then present recent NIRF lymphatic imaging for non-invasive assessment of lymphatics both in preclinical melanoma models and in human subjects with melanoma.
KeywordsImaging Near-infrared fluorescence Lymphatic Metastasis Lymphangiogenesis Optics
Magnetic resonance imaging
Charge coupled device
Positron emission tomography
X-ray computed tomography
Sentinel lymph node
Manual lymphatic drainage
Region of interest
Fetal bovine serum
Investigational new drug application
Institutional review board
Food and Drug Administration
Intensified charge coupled device
The authors acknowledge I-Chih Tan and Banghe Zhu for their technical contributions and Melissa B. Aldrich, Kristen E. Adams, Chinmay Darne, Caroline E. Fife, Renie Guilliod, Milton V. Marshall, Erik A. Maus, Latisha A. Smith, I-Chih Tan, and Banghe Zhu for insightful discussions and participation in the clinical studies. This work was supported in parts by grants from the U.S. National Institutes of Health, National Cancer Institute (R01 CA 128919), the National Cancer Institute Network for Translational Research (U54 CA136404), and the National Heart, Lung, and Blood Institute (R01 HL092923).
Conflict of interest
The authors report no financial conflicts of interest.
- 3.Adams, K. E., J. C. Rasmussen, C. Darne, I.-C. Tan, M. B. Aldrich, M. V. Marshall, C. E. Fife, E. A. Maus, L. A. Smith, R. Guilloid, S. Hoy, and E. M. Sevick-Muraca. Direct evidence of improved lymphatic function following treatment with an advanced pneumatic compression device. Biomed. Opt. Express 1(1):114–125, 2010.PubMedCrossRefGoogle Scholar
- 8.Davies-Venn, C., B. Angermiller, N. Wilganowski, P. Ghosh, B. Harvey, G. Wu, S. Kwon, M. Aldrich, and E. Sevick-Muraca. Albumin-binding domain conjugate for near-infrared fluorescence lymphatic imaging. Mol. Imaging Biol. doi: 10.1007/s11307-011-0499-x.
- 9.Eichholz, A., S. Merchant, and A. M. Gaya. Anti-angiogenesis therapies: their potential in cancer management. OncoTargets Ther. 3(1):69–82, 2010.Google Scholar
- 14.Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies. In: U.S. Department of Health and Human Services, Food and Drug Administration CDER, editors. Rockville, MD ed2006.Google Scholar
- 19.Jain, R. K. Antiangiogenic therapy for cancer: current and emerging concepts. Anglais 19(4 Suppl 3):7–16, 2005.Google Scholar
- 30.Maus, E. A., I. C. Tan, J. C. Rasmussen, M. V. Marshall, C. E. Fife, L. A. Smith, R. Guilliod, and E. M. Sevick-Muraca. Near-infrared fluorescence imaging of lymphatics in head and neck lymphedema. Head Neck. doi: 10.1002/hed.21538.
- 31.Miyashiro, I., N. Miyoshi, M. Hiratsuka, K. Kishi, T. Yamada, M. Ohue, H. Ohigashi, M. Yano, O. Ishikawa, and S. Imaoka. Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann. Surg. Oncol. 15(6):1640–1643, 2008.PubMedCrossRefGoogle Scholar
- 37.Oremus, A., K. Walker, I. Dayes, and P. Raina. Diagnosis and treatment of secondary lymphedema: prepared by McMaster University Evidence-based Practice Center for Agency for Healthcare Research and Quality; Draft version dated October 19, 2009.Google Scholar
- 40.Qian, C. N., B. Berghuis, G. Tsarfaty, M. Bruch, E. J. Kort, J. Ditlev, I. Tsarfaty, E. Hudson, D. G. Jackson, D. Petillo, J. D. Chen, J. H. Resau, and B. T. Teh. Preparing the “soil”: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res. 66(21):10365–10376, 2006.PubMedCrossRefGoogle Scholar
- 46.Schaafsma, B. E., J. S. D. Mieog, M. Hutteman, J. R. van der Vorst, P. J. K. Kuppen, C. W. G. M. Löwik, J. V. Frangioni, C. J. H. van de Velde, and A. L. Vahrmeijer. The clinical use of indocyanine green as a near-infrared fluorescent contrast agent for image-guided oncologic surgery. J. Surg. Oncol. 104(3):323–332, 2011.PubMedCrossRefGoogle Scholar
- 47.Sevick-Muraca, E. M., R. Sharma, J. C. Rasmussen, M. V. Marshall, J. A. Wendt, H. Q. Pham, E. Bonefas, J. P. Houston, L. Sampath, K. E. Adams, D. K. Blanchard, R. E. Fisher, S. B. Chiang, R. Elledge, and M. E. Mawad. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology 246(3):734–741, 2008.PubMedCrossRefGoogle Scholar
- 54.Tan, I. C., E. A. Maus, J. C. Rasmussen, M. V. Marshall, K. E. Adams, C. E. Fife, L. A. Smith, W. Chan, and E. M. Sevick-Muraca. Assessment of lymphatic contractile function after manual lymphatic drainage using near-infrared fluorescence imaging. Arch. Phys. Med. Rehabil. 92(5):756–764.e1, 2011.PubMedCrossRefGoogle Scholar
- 63.Zhu, B., I.-C. Tan, J. C. Rasmussen, and E. M. Sevick-Muraca. Validating the sensitivity and performance of near-infrared fluorescence imaging and tomography devices using a novel solid phantom and measurement approach. Technol. Cancer Res. Treat. (in press).Google Scholar