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Animal models and molecular imaging tools to investigate lymph node metastases

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Abstract

Lymph node metastasis is a strong predictor of poor outcome in cancer patients. Animal studies of lymph node metastasis are constrained by difficulties in the establishment of appropriate animal models, limitations in the noninvasive monitoring of lymph node metastasis progression, and challenges in the pathologic confirmation of lymph node metastases. In this comprehensive review, we summarize available preclinical animal cancer models for noninvasive imaging and identification of lymph node metastases of non-hematogenous cancers. Furthermore, we discuss the strengths and weaknesses of common noninvasive imaging modalities used to identify tumor-bearing lymph nodes and provide guidelines for their pathological confirmation.

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References

  1. Giuliano AE, Kirgan DM, Guenther JM, Morton DL (1994) Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 220:391–398, discussion 398–401

    Article  PubMed  CAS  Google Scholar 

  2. Govindarajan A, Baxter NN (2008) Lymph node evaluation in early-stage colon cancer. Clin Colorectal Cancer 7:240–246. doi:10.3816/CCC.2008.n.031

    Article  PubMed  Google Scholar 

  3. Liptay M (2004) Sentinel node mapping in lung cancer. Ann Surg Oncol 11:271–274S

    Google Scholar 

  4. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, Foshag LJ, Cochran AJ (1992) Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392–399

    PubMed  CAS  Google Scholar 

  5. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648

    PubMed  CAS  Google Scholar 

  6. Krag DN, Single RM (2003) Breast cancer survival according to number of nodes removed. Ann Surg Oncol 10:1152–1159

    Article  PubMed  Google Scholar 

  7. Teicher BA (2006) Tumor models for efficacy determination. Mol Cancer Ther 5:2435–2443. doi:10.1158/1535-7163.MCT-06-0391

    Article  PubMed  CAS  Google Scholar 

  8. Kerbel RS (2003) Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: better than commonly perceived-but they can be improved. Cancer Biol Ther 2:S134–S139

    PubMed  CAS  Google Scholar 

  9. Brader P, Kelly K, Gang S, Shah JP, Wong RJ, Hricak H, Blasberg RG, Fong Y, Gil Z (2009) Imaging of lymph node micrometastases using an oncolytic herpes virus and [F]FEAU PET. PLoS ONE 4:e4789. doi:10.1371/journal.pone.0004789

    Article  PubMed  CAS  Google Scholar 

  10. Harrell MI, Iritani BM, Ruddell A (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774–786. doi:10.2353/ajpath.2007.060761

    Article  PubMed  Google Scholar 

  11. Kelly KJ, Brader P, Woo Y, Li S, Chen N, Yu YA, Szalay AA, Fong Y (2009) Real-time intraoperative detection of melanoma lymph node metastases using recombinant vaccinia virus GLV-1h68 in an immunocompetent animal model. Int J Cancer 124:911–918. doi:10.1002/ijc.24037

    Article  PubMed  CAS  Google Scholar 

  12. Ruddell A, Harrell MI, Minoshima S, Maravilla KR, Iritani BM, White SW, Partridge SC (2008) Dynamic contrast-enhanced magnetic resonance imaging of tumor-induced lymph flow. Neoplasia 10:706–713

    PubMed  Google Scholar 

  13. Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B, Fukumura D, Padera TP, Jain RK (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. doi:10.1158/0008-5472.CAN-06-1392

    Article  PubMed  CAS  Google Scholar 

  14. Rebhun RB, Lazar AJ, Fidler IJ, Gershenwald JE (2008) Impact of sentinel lymphadenectomy on survival in a murine model of melanoma. Clin Exp Metastasis 25:191–199. doi:10.1007/s10585-008-9141-y

    Article  PubMed  Google Scholar 

  15. Moore A, Sergeyev N, Bredow S, Weissleder R (1998) A model system to quantitate tumor burden in locoregional lymph nodes during cancer spread. Invasion Metastasis 18:192–197

    Article  PubMed  Google Scholar 

  16. Wunderbaldinger P, Josephson L, Bremer C, Moore A, Weissleder R (2002) Detection of lymph node metastases by contrast-enhanced MRI in an experimental model. Magn Reson Med 47:292–297. doi:10.1002/mrm.10068

    Article  PubMed  Google Scholar 

  17. Galanzha EI, Shashkov EV, Tuchin VV, Zharov VP (2008) In vivo multispectral, multiparameter, photoacoustic lymph flow cytometry with natural cell focusing, label-free detection and multicolor nanoparticle probes. Cytom A 73:884–894. doi:10.1002/cyto.a.20587

    Article  Google Scholar 

  18. Kobayashi H, Ogawa M, Kosaka N, Choyke PL, Urano Y (2009) Multicolor imaging of lymphatic function with two nanomaterials: quantum dot-labeled cancer cells and dendrimer-based optical agents. Nanomedicine Lond 4:411–419. doi:10.2217/nnm.09.15

    Article  PubMed  CAS  Google Scholar 

  19. Ballou B, Ernst LA, Andreko S, Harper T, Fitzpatrick JA, Waggoner AS, Bruchez MP (2007) Sentinel lymph node imaging using quantum dots in mouse tumor models. Bioconjug Chem 18:389–396. doi:10.1021/bc060261j

    Article  PubMed  CAS  Google Scholar 

  20. Boisgard R, Vincent-Naulleau S, Leplat JJ, Bouet S, Le Chalony C, Tricaud Y, Horak V, Geffrotin C, Frelat G, Tavitian B (2003) A new animal model for the imaging of melanoma: correlation of FDG PET with clinical outcome, macroscopic aspect and histological classification in melanoblastoma-bearing Libechov Minipigs. Eur J Nucl Med Mol Imaging 30:826–834. doi:10.1007/s00259-003-1152-y

    Article  PubMed  Google Scholar 

  21. Goldberg BB, Merton DA, Liu JB, Thakur M, Murphy GF, Needleman L, Tornes A, Forsberg F (2004) Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology 230:727–734. doi:10.1148/radiol.2303021440

    Article  PubMed  Google Scholar 

  22. Tanaka E, Choi HS, Fujii H, Bawendi MG, Frangioni JV (2006) Image-guided oncologic surgery using invisible light: completed pre-clinical development for sentinel lymph node mapping. Ann Surg Oncol 13:1671–1681. doi:10.1245/s10434-006-9194-6

    Article  PubMed  Google Scholar 

  23. Dadiani M, Kalchenko V, Yosepovich A, Margalit R, Hassid Y, Degani H, Seger D (2006) Real-time imaging of lymphogenic metastasis in orthotopic human breast cancer. Cancer Res 66:8037–8041. doi:10.1158/0008-5472.CAN-06-0728

    Article  PubMed  CAS  Google Scholar 

  24. Kobayashi H, Kawamoto S, Bernardo M, Brechbiel MW, Knopp MV, Choyke PL (2006) Delivery of gadolinium-labeled nanoparticles to the sentinel lymph node: comparison of the sentinel node visualization and estimations of intra-nodal gadolinium concentration by the magnetic resonance imaging. J Control Release 111:343–351. doi:10.1016/j.jconrel.2005.12.019

    Article  PubMed  CAS  Google Scholar 

  25. Kobayashi H, Kawamoto S, Sakai Y, Choyke PL, Star RA, Brechbiel MW, Sato N, Tagaya Y, Morris JC, Waldmann TA (2004) Lymphatic drainage imaging of breast cancer in mice by micro-magnetic resonance lymphangiography using a nano-size paramagnetic contrast agent. J Natl Cancer Inst 96:703–708

    Article  PubMed  CAS  Google Scholar 

  26. Eisenberg DP, Adusumilli PS, Hendershott KJ, Chung S, Yu Z, Chan MK, Hezel M, Wong RJ, Fong Y (2006) Real-time intraoperative detection of breast cancer axillary lymph node metastases using a green fluorescent protein-expressing herpes virus. Ann Surg 243:824–830. doi:10.1097/01.sla.0000219738.56896.c0, discussion 830–822

    Article  PubMed  Google Scholar 

  27. Li X, Wang J, An Z, Yang M, Baranov E, Jiang P, Sun F, Moossa AR, Hoffman RM (2002) Optically imageable metastatic model of human breast cancer. Clin Exp Metastasis 19:347–350

    Article  PubMed  CAS  Google Scholar 

  28. Myers JN, Holsinger FC, Jasser SA, Bekele BN, Fidler IJ (2002) An orthotopic nude mouse model of oral tongue squamous cell carcinoma. Clin Cancer Res 8:293–298

    PubMed  Google Scholar 

  29. Melancon MP, Wang Y, Wen X, Bankson JA, Stephens LC, Jasser S, Gelovani JG, Myers JN, Li C (2007) Development of a macromolecular dual-modality MR-optical imaging for sentinel lymph node mapping. Invest Radiol 42:569–578. doi:10.1097/RLI.0b013e31804f5a79

    Article  PubMed  Google Scholar 

  30. Adusumilli PS, Eisenberg DP, Stiles BM, Chung S, Chan MK, Rusch VW, Fong Y (2006) Intraoperative localization of lymph node metastases with a replication-competent herpes simplex virus. J Thorac Cardiovasc Surg 132:1179–1188. doi:10.1016/j.jtcvs.2006.07.005

    Article  PubMed  Google Scholar 

  31. Servais EL, Velez MC, Rusch VW, Sadelain M, Adusumilli PS (2009) A preclinical mouse model of orthotopic pleural cancer that facilitates noninvasive quantitative monitoring of tumor progression and therapy response. Cancer Res 69:B27

    Article  CAS  Google Scholar 

  32. Takizawa H, Kondo K, Toba H, Kenzaki K, Sakiyama S, Tangoku A (2009) Fluorescence diagnosis of lymph node metastasis of lung cancer in a mouse model. Oncol Rep 22:17–21

    PubMed  Google Scholar 

  33. Ishikura H, Kondo K, Miyoshi T, Kinoshita H, Hirose T, Monden Y (2000) Artificial lymphogenous metastatic model using orthotopic implantation of human lung cancer. Ann Thorac Surg 69:1691–1695

    Article  PubMed  CAS  Google Scholar 

  34. Koyama T, Tsubota A, Nariai K, Mitsunaga M, Yanaga K, Takahashi H (2007) Novel biomedical imaging approach for detection of sentinel nodes in an experimental model of gastric cancer. Br J Surg 94:996–1001. doi:10.1002/bjs.5650

    Article  PubMed  CAS  Google Scholar 

  35. Koyama T, Tsubota A, Nariai K, Yoshikawa T, Mitsunaga M, Sumi M, Nimura H, Yanaga K, Yumoto Y, Mabashi Y, Takahashi H (2007) Detection of sentinel nodes by a novel red-fluorescent dye, ATX-S10Na (II), in an orthotopic xenograft rat model of human gastric carcinoma. Lasers Surg Med 39:76–82. doi:10.1002/lsm.20410

    Article  PubMed  Google Scholar 

  36. Bouvet M, Wang J, Nardin SR, Nassirpour R, Yang M, Baranov E, Jiang P, Moossa AR, Hoffman RM (2002) Real-time optical imaging of primary tumor growth and multiple metastatic events in a pancreatic cancer orthotopic model. Cancer Res 62:1534–1540

    PubMed  CAS  Google Scholar 

  37. Katz MH, Bouvet M, Takimoto S, Spivack D, Moossa AR, Hoffman RM (2003) Selective antimetastatic activity of cytosine analog CS-682 in a red fluorescent protein orthotopic model of pancreatic cancer. Cancer Res 63:5521–5525

    PubMed  CAS  Google Scholar 

  38. Kovar JL, Johnson MA, Volcheck WM, Chen J, Simpson MA (2006) Hyaluronidase expression induces prostate tumor metastasis in an orthotopic mouse model. Am J Pathol 169:1415–1426

    Article  PubMed  CAS  Google Scholar 

  39. Narla G, DiFeo A, Fernandez Y, Dhanasekaran S, Huang F, Sangodkar J, Hod E, Leake D, Friedman SL, Hall SJ, Chinnaiyan AM, Gerald WL, Rubin MA, Martignetti JA (2008) KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis. J Clin Invest 118:2711–2721. doi:10.1172/JCI34780

    Article  PubMed  CAS  Google Scholar 

  40. Nwogu CE, Kanter PM, Anderson TM (2002) Pulmonary lymphatic mapping in dogs: use of technetium sulfur colloid and isosulfan blue for pulmonary sentinel lymph node mapping in dogs. Cancer Investig 20:944–947

    Article  Google Scholar 

  41. Song L, Kim C, Maslov K, Shung KK, Wang LV (2009) High-speed dynamic 3D photoacoustic imaging of sentinel lymph node in a murine model using an ultrasound array. Med Phys 36:3724–3729

    Article  PubMed  Google Scholar 

  42. Bergqvist L, Strand SE, Persson BR (1983) Particle sizing and biokinetics of interstitial lymphoscintigraphic agents. Semin Nucl Med 13:9–19

    Article  PubMed  CAS  Google Scholar 

  43. Soltesz EG, Kim S, Laurence RG, DeGrand AM, Parungo CP, Dor DM, Cohn LH, Bawendi MG, Frangioni JV, Mihaljevic T (2005) Intraoperative sentinel lymph node mapping of the lung using near-infrared fluorescent quantum dots. Ann Thorac Surg 79:269–277. doi:10.1016/j.athoracsur.2004.06.055, discussion 269–277

    Article  PubMed  Google Scholar 

  44. Alazraki NP, Eshima D, Eshima LA, Herda SC, Murray DR, Vansant JP, Taylor AT (1997) Lymphoscintigraphy, the sentinel node concept, and the intraoperative gamma probe in melanoma, breast cancer, and other potential cancers. Semin Nucl Med 27:55–67

    Article  PubMed  CAS  Google Scholar 

  45. Jain R, Dandekar P, Patravale V (2009) Diagnostic nanocarriers for sentinel lymph node imaging. J Control Release 138:90–102. doi:10.1016/j.jconrel.2009.05.010

    Article  PubMed  CAS  Google Scholar 

  46. Bar J, Herbst R, Onn A (2009) Targeted drug delivery strategies to treat lung metastasis. Expert Opin Drug Deliv 6:1003–1016

    Article  PubMed  CAS  Google Scholar 

  47. Dieter M, Schubert R, Hirnle P (2003) Blue liposomes for identification of the sentinel lymph nodes in pigs. Lymphology 36:39–47

    PubMed  CAS  Google Scholar 

  48. Hirnle P, Harzmann R, Wright JK (1988) Patent blue V encapsulation in liposomes: potential applicability to endolympatic therapy and preoperative chromolymphography. Lymphology 21:187–189

    PubMed  CAS  Google Scholar 

  49. Pump B, Hirnle P (1996) Preoperative lymph-node staining with liposomes containing patent blue violet. A clinical case report. J Pharm Pharmacol 48:699–701

    Article  PubMed  CAS  Google Scholar 

  50. Phillips WT, Klipper R, Goins B (2001) Use of (99m)Tc-labeled liposomes encapsulating blue dye for identification of the sentinel lymph node. J Nucl Med 42:446–451

    PubMed  CAS  Google Scholar 

  51. Wang Y, Cheng Z, Li J, Tang J (2009) Gray-scale contrast-enhanced utrasonography in detecting sentinel lymph nodes: an animal study. Eur J Radiol. doi:10.1016/j.ejrad.2009.03.063

    Google Scholar 

  52. Wisner ER, Ferrara KW, Short RE, Ottoboni TB, Gabe JD, Patel D (2003) Sentinel node detection using contrast-enhanced power doppler ultrasound lymphography. Invest Radiol 38:358–365

    PubMed  Google Scholar 

  53. Wang LV (2008) Prospects of photoacoustic tomography. Med Phys 35:5758–5767

    Article  PubMed  Google Scholar 

  54. Song KH, Stein EW, Margenthaler JA, Wang LV (2008) Noninvasive photoacoustic identification of sentinel lymph nodes containing methylene blue in vivo in a rat model. J Biomed Opt 13:054033. doi:10.1117/1.2976427

    Article  PubMed  Google Scholar 

  55. Kim S, Lim YT, Soltesz EG, De Grand AM, Lee J, Nakayama A, Parker JA, Mihaljevic T, Laurence RG, Dor DM, Cohn LH, Bawendi MG, Frangioni JV (2004) Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol 22:93–97. doi:10.1038/nbt920nbt920

    Article  PubMed  CAS  Google Scholar 

  56. Dahan M, Laurence T, Pinaud F, Chemla DS, Alivisatos AP, Sauer M, Weiss S (2001) Time-gated biological imaging by use of colloidal quantum dots. Opt Lett 26:825–827

    Article  PubMed  CAS  Google Scholar 

  57. Biju V, Itoh T, Anas A, Sujith A, Ishikawa M (2008) Semiconductor quantum dots and metal nanoparticles: syntheses, optical properties, and biological applications. Anal Bioanal Chem 391:2469–2495. doi:10.1007/s00216-008-2185-7

    Article  PubMed  CAS  Google Scholar 

  58. Parungo CP, Colson YL, Kim SW, Kim S, Cohn LH, Bawendi MG, Frangioni JV (2005) Sentinel lymph node mapping of the pleural space. Chest 127:1799–1804. doi:10.1378/chest.127.5.1799

    Article  PubMed  Google Scholar 

  59. Parungo CP, Ohnishi S, Kim SW, Kim S, Laurence RG, Soltesz EG, Chen FY, Colson YL, Cohn LH, Bawendi MG, Frangioni JV (2005) Intraoperative identification of esophageal sentinel lymph nodes with near-infrared fluorescence imaging. J Thorac Cardiovasc Surg 129:844–850. doi:10.1016/j.jtcvs.2004.08.001

    Article  PubMed  Google Scholar 

  60. Hardman R (2006) A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ Health Perspect 114:165–172

    Article  PubMed  Google Scholar 

  61. Vakoc BJ, Lanning RM, Tyrrell JA, Padera TP, Bartlett LA, Stylianopoulos T, Munn LL, Tearney GJ, Fukumura D, Jain RK, Bouma BE (2009) Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat Med 15:1219–1223. doi:10.1038/nm.1971

    Article  PubMed  CAS  Google Scholar 

  62. McElroy M, Hayashi K, Garmy-Susini B, Kaushal S, Varner JA, Moossa AR, Hoffman RM, Bouvet M (2009) Fluorescent LYVE-1 antibody to image dynamically lymphatic trafficking of cancer cells in vivo. J Surg Res 151:68–73. doi:10.1016/j.jss.2007.12.769

    Article  PubMed  CAS  Google Scholar 

  63. Gleysteen JP, Newman JR, Chhieng D, Frost A, Zinn KR, Rosenthal EL (2008) Fluorescent labeled anti-EGFR antibody for identification of regional and distant metastasis in a preclinical xenograft model. Head Neck 30:782–789. doi:10.1002/hed.20782

    Article  PubMed  Google Scholar 

  64. Mumprecht V, Honer M, Vigl B, Proulx ST, Trachsel E, Kaspar M, Banziger-Tobler NE, Schibli R, Neri D, Detmar M (2010) In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography. Cancer Res 70:8842–8851. doi:10.1158/0008-5472.CAN-10-0896

    Article  PubMed  CAS  Google Scholar 

  65. Zou P, Xu S, Povoski SP, Wang A, Johnson MA, Martin EW Jr, Subramaniam V, Xu R, Sun D (2009) Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice. Mol Pharm 6:428–440. doi:10.1021/mp9000052

    Article  PubMed  CAS  Google Scholar 

  66. Huyn ST, Burton JB, Sato M, Carey M, Gambhir SS, Wu L (2009) A potent, imaging adenoviral vector driven by the cancer-selective mucin-1 promoter that targets breast cancer metastasis. Clin Cancer Res 15:3126–3134. doi:10.1158/1078-0432.CCR-08-2666

    Article  PubMed  CAS  Google Scholar 

  67. Grillot-Courvalin C, Goussard S, Huetz F, Ojcius DM, Courvalin P (1998) Functional gene transfer from intracellular bacteria to mammalian cells. Nat Biotechnol 16:862–866. doi:10.1038/nbt0998-862

    Article  PubMed  CAS  Google Scholar 

  68. Adusumilli PS, Stiles BM, Chan MK, Mullerad M, Eisenberg DP, Ben-Porat L, Huq R, Rusch VW, Fong Y (2006) Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses. J Gene Med 8:603–615. doi:10.1002/jgm.877

    Article  PubMed  CAS  Google Scholar 

  69. Stiles BM, Adusumilli PS, Bhargava A, Stanziale SF, Kim TH, Chan MK, Huq R, Wong R, Rusch VW, Fong Y (2006) Minimally invasive localization of oncolytic herpes simplex viral therapy of metastatic pleural cancer. Cancer Gene Ther 13:53–64. doi:10.1038/sj.cgt.7700860

    Article  PubMed  CAS  Google Scholar 

  70. Burton JB, Johnson M, Sato M, Koh SB, Mulholland DJ, Stout D, Chatziioannou AF, Phelps ME, Wu H, Wu L (2008) Adenovirus-mediated gene expression imaging to directly detect sentinel lymph node metastasis of prostate cancer. Nat Med 14:882–888. doi:10.1038/nm.1727

    Article  PubMed  CAS  Google Scholar 

  71. Serganova I, Ponomarev V, Blasberg R (2007) Human reporter genes: potential use in clinical studies. Nucl Med Biol 34:791–807. doi:10.1016/j.nucmedbio.2007.05.009

    Article  PubMed  CAS  Google Scholar 

  72. Kishimoto H, Kojima T, Watanabe Y, Kagawa S, Fujiwara T, Uno F, Teraishi F, Kyo S, Mizuguchi H, Hashimoto Y, Urata Y, Tanaka N (2006) In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus. Nat Med 12:1213–1219. doi:10.1038/nm1404

    Article  PubMed  CAS  Google Scholar 

  73. Ntziachristos V, Ripoll J, Wang LV, Weissleder R (2005) Looking and listening to light: the evolution of whole-body photonic imaging. Nat Biotechnol 23:313–320. doi:10.1038/nbt1074

    Article  PubMed  CAS  Google Scholar 

  74. Swirski FK, Berger CR, Figueiredo JL, Mempel TR, von Andrian UH, Pittet MJ, Weissleder R (2007) A near-infrared cell tracker reagent for multiscopic in vivo imaging and quantification of leukocyte immune responses. PLoS ONE 2:e1075. doi:10.1371/journal.pone.0001075

    Article  PubMed  CAS  Google Scholar 

  75. Lee KC, Moon WK, Chung JW, Choi SH, Cho N, Cha JH, Lee EH, Kim SM, Kim HS, Han MH, Chang KH (2007) Assessment of lymph node metastases by contrast-enhanced MR imaging in a head and neck cancer model. Korean J Radiol 8:9–14

    Article  PubMed  Google Scholar 

  76. Choi SH, Han MH, Moon WK, Son KR, Won JK, Kim JH, Kwon BJ, Na DG, Weinmann HJ, Chang KH (2006) Cervical lymph node metastases: MR imaging of gadofluorine M and monocrystalline iron oxide nanoparticle-47 in a rabbit model of head and neck cancer. Radiology 241:753–762. doi:10.1148/radiol.2413051979

    Article  PubMed  Google Scholar 

  77. Paroo Z, Bollinger RA, Braasch DA, Richer E, Corey DR, Antich PP, Mason RP (2004) Validating bioluminescence imaging as a high-throughput, quantitative modality for assessing tumor burden. Mol Imaging 3:117–124. doi:10.1162/1535350041464865

    Article  PubMed  Google Scholar 

  78. Zabala M, Alzuguren P, Benavides C, Crettaz J, Gonzalez-Aseguinolaza G, Ortiz de Solorzano C, Gonzalez-Aparicio M, Kramer MG, Prieto J, Hernandez-Alcoceba R (2009) Evaluation of bioluminescent imaging for noninvasive monitoring of colorectal cancer progression in the liver and its response to immunogene therapy. Mol Cancer 8:2. doi:10.1186/1476-4598-8-2

    Article  PubMed  CAS  Google Scholar 

  79. Servais EL, Colovos C, Kachala SS, Adusumilli PS (2011) Pre-clinical mouse models of primary and metastatic pleural cancers of the lung and breast. Current protocols in pharmacology and drug delivery (in press)

  80. Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M (2010) Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther 18:413–420. doi:10.1038/mt.2009.210

    Article  PubMed  CAS  Google Scholar 

  81. Luker GD, Luker KE (2008) Optical imaging: current applications and future directions. J Nucl Med 49:1–4. doi:10.2967/jnumed.107.045799

    Article  PubMed  Google Scholar 

  82. Miloud T, Henrich C, Hammerling GJ (2007) Quantitative comparison of click beetle and firefly luciferases for in vivo bioluminescence imaging. J Biomed Opt 12:054018. doi:10.1117/1.2800386

    Article  PubMed  CAS  Google Scholar 

  83. Blasberg RG (2003) In vivo molecular-genetic imaging: multi-modality nuclear and optical combinations. Nucl Med Biol 30:879–888

    Article  PubMed  CAS  Google Scholar 

  84. Dobrenkov K, Olszewska M, Likar Y, Shenker L, Gunset G, Cai S, Pillarsetty N, Hricak H, Sadelain M, Ponomarev V (2008) Monitoring the efficacy of adoptively transferred prostate cancer-targeted human T lymphocytes with PET and bioluminescence imaging. J Nucl Med 49:1162–1170. doi:10.2967/jnumed.107.047324

    Article  PubMed  Google Scholar 

  85. Santos EB, Yeh R, Lee J, Nikhamin Y, Punzalan B, La Perle K, Larson SM, Sadelain M, Brentjens RJ (2009) Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase. Nat Med 15:338–344. doi:10.1038/nm.1930

    Article  PubMed  CAS  Google Scholar 

  86. Contag CH, Jenkins D, Contag PR, Negrin RS (2000) Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia 2:41–52

    Article  PubMed  CAS  Google Scholar 

  87. Jenkins D, Oei Y, Hornig Y, Yu S-F, Dusich J, Purchio T, Contag P (2003) Bioluminescent imaging (BLI) to improve and refine traditional murine models of tumor growth and metastasis. Clin Exp Metastasis 20:733–744

    Article  PubMed  CAS  Google Scholar 

  88. Haley P, Perry R, Ennulat D, Frame S, Johnson C, Lapointe JM, Nyska A, Snyder P, Walker D, Walter G (2005) STP position paper: best practice guideline for the routine pathology evaluation of the immune system. Toxicol Pathol 33:404–407. doi:10.1080/01926230590934304, discussion 408

    Article  PubMed  CAS  Google Scholar 

  89. Van den Broeck W, Derore A, Simoens P (2006) Anatomy and nomenclature of murine lymph nodes: descriptive study and nomenclatory standardization in BALB/cAnNCrl mice. J Immunol Methods 312:12–19. doi:10.1016/j.jim.2006.01.022

    Article  PubMed  CAS  Google Scholar 

  90. Willard-Mack CL (2006) Normal structure, function, and histology of lymph nodes. Toxicol Pathol 34:409–424. doi:10.1080/01926230600867727

    Article  PubMed  Google Scholar 

  91. Yamasaki T, Wakabayashi S, Inoue O, Ando K, Kusakabe K, Kawasaki Y, Okamoto S, Taniguchi M (1987) Specific biodetection of B16 mouse melanoma in vivo by syngeneic monoclonal antibody. J Invest Dermatol 89:225–229

    Article  PubMed  CAS  Google Scholar 

  92. Foster PJ, Dunn EA, Karl KE, Snir JA, Nycz CM, Harvey AJ, Pettis RJ (2008) Cellular magnetic resonance imaging: in vivo imaging of melanoma cells in lymph nodes of mice. Neoplasia 10:207–216

    PubMed  CAS  Google Scholar 

  93. Shu CJ, Radu CG, Shelly SM, Vo DD, Prins R, Ribas A, Phelps ME, Witte ON (2009) Quantitative PET reporter gene imaging of CD8+ T cells specific for a melanoma-expressed self-antigen. Int Immunol 21:155–165. doi:10.1093/intimm/dxn133

    Article  PubMed  CAS  Google Scholar 

  94. Jansen SA, Conzen SD, Fan X, Krausz T, Zamora M, Foxley S, River J, Newstead GM, Karczmar GS (2008) Detection of in situ mammary cancer in a transgenic mouse model: in vitro and in vivo MRI studies demonstrate histopathologic correlation. Phys Med Biol 53:5481–5493. doi:10.1088/0031-9155/53/19/014

    Article  PubMed  CAS  Google Scholar 

  95. Wahl RL, Wissing J, del Rosario R, Zasadny KR (1990) Inhibition of autoradiolysis of radiolabeled monoclonal antibodies by cryopreservation. J Nucl Med 31:84–89

    PubMed  CAS  Google Scholar 

  96. Wang L, Yao Q, Wang J, Wei G, Li G, Li D, Ling R, Chen J (2008) MRI and hybrid PET/CT for monitoring tumour metastasis in a metastatic breast cancer model in rabbit. Nucl Med Commun 29:137–143. doi:10.1097/MNM.0b013e3282f258c1

    Article  PubMed  Google Scholar 

  97. Wang Y, Wang W, Li J, Tang J (2009) Gray-scale contrast-enhanced ultrasonography of sentinel lymph nodes in a metastatic breast cancer model. Acad Radiol 16:957–962. doi:10.1016/j.acra.2009.03.007

    Article  PubMed  Google Scholar 

  98. Harrell JC, Dye WW, Harvell DM, Pinto M, Jedlicka P, Sartorius CA, Horwitz KB (2007) Estrogen insensitivity in a model of estrogen receptor positive breast cancer lymph node metastasis. Cancer Res 67:10582–10591. doi:10.1158/0008-5472.CAN-07-1655

    Article  PubMed  CAS  Google Scholar 

  99. Winnard PT Jr, Kluth JB, Raman V (2006) Noninvasive optical tracking of red fluorescent protein-expressing cancer cells in a model of metastatic breast cancer. Neoplasia 8:796–806. doi:10.1593/neo.06304

    Article  PubMed  CAS  Google Scholar 

  100. Jenkins DE, Hornig YS, Oei Y, Dusich J, Purchio T (2005) Bioluminescent human breast cancer cell lines that permit rapid and sensitive in vivo detection of mammary tumors and multiple metastases in immune deficient mice. Breast Cancer Res 7:R444–R454. doi:10.1186/bcr1026

    Article  PubMed  CAS  Google Scholar 

  101. Kurihara Y, Watanabe Y, Onimatsu H, Kojima T, Shirota T, Hatori M, Liu D, Kyo S, Mizuguchi H, Urata Y, Shintani S, Fujiwara T (2009) Telomerase-specific virotheranostics for human head and neck cancer. Clin Cancer Res 15:2335–2343. doi:10.1158/1078-0432.CCR-08-2690

    Article  PubMed  CAS  Google Scholar 

  102. Moral M, Segrelles C, Lara MF, Martinez-Cruz AB, Lorz C, Santos M, Garcia-Escudero R, Lu J, Kiguchi K, Buitrago A, Costa C, Saiz C, Rodriguez-Peralto JL, Martinez-Tello FJ, Rodriguez-Pinilla M, Sanchez-Cespedes M, Garin M, Grande T, Bravo A, DiGiovanni J, Paramio JM (2009) Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma. Cancer Res 69:1099–1108. doi:10.1158/0008-5472.CAN-08-3240

    Article  PubMed  CAS  Google Scholar 

  103. Shomura Y, Saito Y, Minami K, Imamura H (2003) A new method for establishing an intrapulmonary tumor in the rabbit. Jpn J Thorac Cardiovasc Surg 51:337–343. doi:10.1007/BF02719464

    Article  PubMed  Google Scholar 

  104. Murayama Y, Harada Y, Imaizumi K, Dai P, Nakano K, Okamoto K, Otsuji E, Takamatsu T (2009) Precise detection of lymph node metastases in mouse rectal cancer by using 5-aminolevulinic acid. Int J Cancer 125:2256–2263. doi:10.1002/ijc.24707

    Article  PubMed  CAS  Google Scholar 

  105. Shah SA, Gallagher BM, Sands H (1987) Lymphoscintigraphy of human colorectal carcinoma metastases in athymic mice by use of radioiodinated B72.3 monoclonal antibody. J Natl Cancer Inst 78:1069–1077

    PubMed  CAS  Google Scholar 

  106. Ohsawa I, Murakami T, Uemoto S, Kobayashi E (2006) In vivo luminescent imaging of cyclosporin A-mediated cancer progression in rats. Transplantation 81:1558–1567. doi:10.1097/01.tp.0000209448.50238.de

    Article  PubMed  CAS  Google Scholar 

  107. Stelter L, Amthauer H, Rexin A, Pinkernelle J, Schulz P, Michel R, Denecke T, Stiepani H, Hamm B, Wiedenmann B, Scholz A (2008) An orthotopic model of pancreatic somatostatin receptor (SSTR)-positive tumors allows bimodal imaging studies using 3T MRI and animal PET-based molecular imaging of SSTR expression. Neuroendocrinology 87:233–242. doi:10.1159/000111502

    Article  PubMed  CAS  Google Scholar 

  108. Hayashi K, Zhao M, Yamauchi K, Yamamoto N, Tsuchiya H, Tomita K, Hoffman RM (2009) Cancer metastasis directly eradicated by targeted therapy with a modified Salmonella typhimurium. J Cell Biochem 106:992–998. doi:10.1002/jcb.22078

    Article  PubMed  CAS  Google Scholar 

  109. Hsieh CL, Xie Z, Yu J, Martin WD, Datta MW, Wu GJ, Chung LW (2007) Non-invasive bioluminescent detection of prostate cancer growth and metastasis in a bigenic transgenic mouse model. Prostate 67:685–691. doi:10.1002/pros.20510

    Article  PubMed  Google Scholar 

  110. van Leeuwen AC, Buckle T, Bendle G, Vermeeren L, Valdes Olmos R, van de Poel HG, van Leeuwen FW (2011) Tracer-cocktail injections for combined pre- and intraoperative multimodal imaging of lymph nodes in a spontaneous mouse prostate tumor model. J Biomed Opt 16:016004. doi:10.1117/1.3528027

    Article  PubMed  CAS  Google Scholar 

  111. Vassallo P, Matei C, Heston WD, McLachlan SJ, Koutcher JA, Castellino RA (1995) Characterization of reactive versus tumor-bearing lymph nodes with interstitial magnetic resonance lymphography in an animal model. Invest Radiol 30:706–711

    Article  PubMed  CAS  Google Scholar 

  112. La Perle KM, Shen D, Buckwalter TL, Williams B, Haynam A, Hinkle G, Pozderac R, Capen CC, Jhiang SM (2002) In vivo expression and function of the sodium iodide symporter following gene transfer in the MATLyLu rat model of metastatic prostate cancer. Prostate 50:170–178. doi:10.1002/pros.10046

    Article  PubMed  CAS  Google Scholar 

  113. Nathanson SD, Haas GP, Mead MJ, Lee M (1986) Spontaneous regional lymph node metastases of three variants of the B16 melanoma: relationship to primary tumor size and pulmonary metastases. J Surg Oncol 33:41–45

    Article  PubMed  CAS  Google Scholar 

  114. Man S, Munoz R, Kerbel RS (2007) On the development of models in mice of advanced visceral metastatic disease for anti-cancer drug testing. Cancer Metastasis Rev 26:737–747. doi:10.1007/s10555-007-9087-6

    Article  PubMed  Google Scholar 

  115. Sun R, Zhang JG, Guo CB (2008) Establishment of cervical lymph node metastasis model of squamous cell carcinoma in the oral cavity in mice. Chin Med J Engl 121:1891–1895

    PubMed  Google Scholar 

  116. Matsui T, Ota T, Ueda Y, Tanino M, Odashima S (1998) Isolation of a highly metastatic cell line to lymph node in human oral squamous cell carcinoma by orthotopic implantation in nude mice. Oral Oncol 34:253–256

    PubMed  CAS  Google Scholar 

  117. Maekawa K, Sato H, Furukawa M, Yoshizaki T (2002) Inhibition of cervical lymph node metastasis by marimastat (BB-2516) in an orthotopic oral squamous cell carcinoma implantation model. Clin Exp Metastasis 19:513–518

    Article  PubMed  CAS  Google Scholar 

  118. Yu Z, Chan MK, Oc P, Eisenberg DP, Shah JP, Singh B, Fong Y, Wong RJ (2005) Enhanced nectin-1 expression and herpes oncolytic sensitivity in highly migratory and invasive carcinoma. Clin Cancer Res 11:4889–4897. doi:10.1158/1078-0432.CCR-05-0309

    Article  PubMed  CAS  Google Scholar 

  119. Liu J, Blackhall F, Seiden-Long I, Jurisica I, Navab R, Liu N, Radulovich N, Wigle D, Sultan M, Hu J, Tsao MS, Johnston MR (2004) Modeling of lung cancer by an orthotopically growing H460SM variant cell line reveals novel candidate genes for systemic metastasis. Oncogene 23:6316–6324. doi:10.1038/sj.onc.12077951207795

    Article  PubMed  CAS  Google Scholar 

  120. Doki Y, Murakami K, Yamaura T, Sugiyama S, Misaki T, Saiki I (1999) Mediastinal lymph node metastasis model by orthotopic intrapulmonary implantation of Lewis lung carcinoma cells in mice. Br J Cancer 79:1121–1126. doi:10.1038/sj.bjc.6690178

    Article  PubMed  CAS  Google Scholar 

  121. Bouvet M, Yang M, Nardin S, Wang X, Jiang P, Baranov E, Moossa AR, Hoffman RM (2000) Chronologically-specific metastatic targeting of human pancreatic tumors in orthotopic models. Clin Exp Metastasis 18:213–218

    Article  PubMed  CAS  Google Scholar 

  122. Fujihara T, Sawada T, Hirakawa K, Chung YS, Yashiro M, Inoue T, Sowa M (1998) Establishment of lymph node metastatic model for human gastric cancer in nude mice and analysis of factors associated with metastasis. Clin Exp Metastasis 16:389–398

    Article  PubMed  CAS  Google Scholar 

  123. Mulshine JL, Keenan AM, Carrasquillo JA, Walsh T, Linnoila RI, Holton OD, Harwell J, Larson SM, Bunn PA, Weinstein JN (1987) Immunolymphoscintigraphy of pulmonary and mediastinal lymph nodes in dogs: a new approach to lung cancer imaging. Cancer Res 47:3572–3576

    PubMed  CAS  Google Scholar 

  124. Ueno H, Hihara J, Shimizu K, Osaki A, Yamashita Y, Yoshida K, Toge T (2005) Experimental study on fluorescent microspheres as a tracer for sentinel node detection. Anticancer Res 25:821–825

    PubMed  Google Scholar 

  125. Troyan SL, Kianzad V, Gibbs-Strauss SL, Gioux S, Matsui A, Oketokoun R, Ngo L, Khamene A, Azar F, Frangioni JV (2009) The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann Surg Oncol 16:2943–2952. doi:10.1245/s10434-009-0594-2

    Article  PubMed  Google Scholar 

  126. Long CM, van Laarhoven HW, Bulte JW, Levitsky HI (2009) Magnetovaccination as a novel method to assess and quantify dendritic cell tumor antigen capture and delivery to lymph nodes. Cancer Res 69:3180–3187. doi:10.1158/0008-5472.CAN-08-3691

    Article  PubMed  CAS  Google Scholar 

  127. Koyama Y, Talanov VS, Bernardo M, Hama Y, Regino CA, Brechbiel MW, Choyke PL, Kobayashi H (2007) A dendrimer-based nanosized contrast agent dual-labeled for magnetic resonance and optical fluorescence imaging to localize the sentinel lymph node in mice. J Magn Reson Imaging 25:866–871. doi:10.1002/jmri.20852

    Article  PubMed  Google Scholar 

  128. Wahl RL, Kaminski MS, Ethier SP, Hutchins GD (1990) The potential of 2-deoxy-2[18F]fluoro-d-glucose (FDG) for the detection of tumor involvement in lymph nodes. J Nucl Med 31:1831–1835

    PubMed  CAS  Google Scholar 

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Acknowledgments

Funding

This study was supported in part by American Association for Cancer Research (AACR) Translational Research Award, American Association for Thoracic Surgery (AATS)—Third Edward D. Churchill Research Scholarship, IASLC—International Association for the Study of Lung Cancer Young Investigator Award, National Lung Cancer Partnership/LUNGevity Foundation Research Grant, New York State Empire Clinical Research Investigator Program (ECRIP), Mesothelioma Applied Research Foundation (MARF), grant in memory of Lance S. Ruble and Stony Wold-Herbert Fund, and William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center.

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The authors declare no competing financial interests.

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Correspondence to Prasad S. Adusumilli.

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Elliot L. Servais and Christos Colovos contributed equally to this work.

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Immunodeficient mouse hosts (DOC 55 kb)

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Servais, E.L., Colovos, C., Bograd, A.J. et al. Animal models and molecular imaging tools to investigate lymph node metastases. J Mol Med 89, 753–769 (2011). https://doi.org/10.1007/s00109-011-0764-0

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