Temporal characterization of lymphatic metastasis in an orthotopic mouse model of oral cancer
Peter Szaniszlo MD, PhD
Department of Otolaryngology, UTMB Health Cancer Center, Galveston, Texas
UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorSusan M. Fennewald PhD
Department of Otolaryngology, UTMB Health Cancer Center, Galveston, Texas
UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorSuimin Qiu MD, PhD
UTMB Health Cancer Center, Galveston, Texas
Department of Pathology, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorCarla Kantara PhD
UTMB Health Cancer Center, Galveston, Texas
Department of Neuroscience and Cell Biology, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorTuya Shilagard MS
Center for Biomedical Engineering, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorGracie Vargas PhD
Center for Biomedical Engineering, UTMB Health Cancer Center, Galveston, Texas
Department of Neuroscience and Cell Biology, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorCorresponding Author
Vicente A. Resto MD, PhD
Department of Otolaryngology, UTMB Health Cancer Center, Galveston, Texas
UTMB Health Cancer Center, Galveston, Texas
Department of Biochemistry and Molecular Biology, UTMB Health Cancer Center, Galveston, Texas
Corresponding author: V. A. Resto, Department of Otolaryngology, UTMB Health, 301 University Blvd., Galveston, TX 77555-0521. E-mail: [email protected]Search for more papers by this authorPeter Szaniszlo MD, PhD
Department of Otolaryngology, UTMB Health Cancer Center, Galveston, Texas
UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorSusan M. Fennewald PhD
Department of Otolaryngology, UTMB Health Cancer Center, Galveston, Texas
UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorSuimin Qiu MD, PhD
UTMB Health Cancer Center, Galveston, Texas
Department of Pathology, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorCarla Kantara PhD
UTMB Health Cancer Center, Galveston, Texas
Department of Neuroscience and Cell Biology, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorTuya Shilagard MS
Center for Biomedical Engineering, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorGracie Vargas PhD
Center for Biomedical Engineering, UTMB Health Cancer Center, Galveston, Texas
Department of Neuroscience and Cell Biology, UTMB Health Cancer Center, Galveston, Texas
Search for more papers by this authorCorresponding Author
Vicente A. Resto MD, PhD
Department of Otolaryngology, UTMB Health Cancer Center, Galveston, Texas
UTMB Health Cancer Center, Galveston, Texas
Department of Biochemistry and Molecular Biology, UTMB Health Cancer Center, Galveston, Texas
Corresponding author: V. A. Resto, Department of Otolaryngology, UTMB Health, 301 University Blvd., Galveston, TX 77555-0521. E-mail: [email protected]Search for more papers by this authorThis work was presented in part at the 8th International Conference on Head and Neck Cancer, American Head and Neck Society, Toronto, Ontario, Canada, July 21–25, 2012.
Abstract
Background
The overall mortality rate in cases of head and neck squamous cell carcinoma (HNSCC) has not improved over the past 30 years, mostly because of the high treatment failure rate among patients with regionally metastatic disease. To better understand the pathobiologic processes leading to lymphatic metastasis development, there is an urgent need for relevant animal models.
Methods
HNSCC cell lines were implanted into the tongues of athymic nude mice. Histology, immunohistochemistry, and ex vivo 2-photon microscopy were used to evaluate tumor progress and spread.
Results
Orthotopic xenografts of different HNSCC cell lines produced distinct patterns of survival, tumor histology, disease progression rate, and lymph node metastasis development. Remarkably, all injected cell types reached the lymph nodes within 24 hours after injection, but not all developed metastasis.
Conclusion
This orthotopic xenograft model closely mimics several characteristics of human cancer and could be extremely valuable for translational studies focusing on lymphatic metastasis development and pathobiology. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1638–1647, 2014
REFERENCES
- 1Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
- 2Elferink LA, Resto VA. Receptor-tyrosine-kinase-targeted therapies for head and neck cancer. J Signal Transduct 2011; 2011: 982879.
- 3Dünne AA, Müller HH, Eisele DW, Kessel K, Moll R, Werner JA. Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients. Eur J Cancer 2006; 42: 1863–1868.
- 4Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29.
- 5Law JH, Whigham AS, Wirth PS, et al. Human-in-mouse modeling of primary head and neck squamous cell carcinoma. Laryngoscope 2009; 119: 2315–2323.
- 6Hardisson D. Molecular pathogenesis of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2003; 260: 502–508.
- 7Yan M, Xu Q, Zhang P, Zhou XJ, Zhang ZY, Chen WT. Correlation of NF-kappaB signal pathway with tumor metastasis of human head and neck squamous cell carcinoma. BMC Cancer 2010; 10: 437.
- 8Goldson TM, Han Y, Knight KB, Weiss HL, Resto VA. Clinicopathological predictors of lymphatic metastasis in HNSCC: implications for molecular mechanisms of metastatic disease. J Exp Ther Oncol 2010; 8: 211–221.
- 9Layland MK, Sessions DG, Lenox J. The influence of lymph node metastasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus N+. Laryngoscope 2005; 115: 629–639.
- 10Deschamps DR, Spencer HJ, Kokoska MS, Spring PM, Vural EA, Stack BC Jr. Implications of head and neck cancer treatment failure in the neck. Otolaryngol Head Neck Surg 2010; 142: 722–727.
- 11Howell GM, Grandis JR. Molecular mediators of metastasis in head and neck squamous cell carcinoma. Head Neck 2005; 27: 710–717.
- 12Stoeckli SJ, Alkureishi LW, Ross GL. Sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 2009; 266: 787–793.
- 13Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol 2005; 16 Suppl 6: vi7–vi12.
- 14Sano D, Myers JN. Xenograft models of head and neck cancers. Head Neck Oncol 2009; 1: 32.
- 15Lu SL, Herrington H, Wang XJ. Mouse models for human head and neck squamous cell carcinomas. Head Neck 2006; 28: 945–954.
- 16Povlsen CO, Rygaard J. Heterotransplantation of human epidermoid carcinomas to the mouse mutant nude. Acta Pathol Microbiol Scand A 1972; 80: 713–717.
- 17Povlsen CO, Rygaard J. Heterotransplantation of human adenocarcinomas of the colon and rectum to the mouse mutant nude. A study of nine consecutive transplantations. Acta Pathol Microbiol Scand A 1971; 79: 159–169.
- 18Killion JJ, Radinsky R, Fidler IJ. Orthotopic models are necessary to predict therapy of transplantable tumors in mice. Cancer Metastasis Rev 1998; 17: 279–284.
- 19Kokorina NA, Lewis JS Jr, Zakharkin SO, Krebsbach PH, Nussenbaum B. rhBMP-2 has adverse effects on human oral carcinoma cell lines in vivo. Laryngoscope 2012; 122: 95–102.
- 20Knowles JA, Golden B, Yan L, Carroll WR, Helman EE, Rosenthal EL. Disruption of the AKT pathway inhibits metastasis in an orthotopic model of head and neck squamous cell carcinoma. Laryngoscope 2011; 121: 2359–2365.
- 21Sun J, Shilagard T, Bell B, Motamedi M, Vargas G. In vivo multimodal nonlinear optical imaging of mucosal tissue. Opt Express 2004; 12: 2478–2486.
- 22Rheinwald JG, Hahn WC, Ramsey MR, et al. A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status. Mol Cell Biol 2002; 22: 5157–5172.
- 23Richmond A, Su Y. Mouse xenograft models vs GEM models for human cancer therapeutics. Dis Model Mech 2008; 1: 78–82.
- 24Hawkins BL, Heniford BW, Ackermann DM, Leonberger M, Martinez SA, Hendler FJ. 4NQO carcinogenesis: a mouse model of oral cavity squamous cell carcinoma. Head Neck 1994; 16: 424–432.
- 25Kanojia D, Vaidya MM. 4-nitroquinoline-1-oxide induced experimental oral carcinogenesis. Oral Oncol 2006; 42: 655–667.
- 26Fracalossi AC, Comparini L, Funabashi K, et al. Ras gene mutation is not related to tumour invasion during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. J Oral Pathol Med 2011; 40: 325–333.
- 27Opitz OG, Harada H, Suliman Y, et al. A mouse model of human oral-esophageal cancer. J Clin Invest 2002; 110: 761–769.
- 28Lu SL, Reh D, Li AG, et al. Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res 2004; 64: 4405–4410.
- 29Lu SL, Herrington H, Reh D, et al. Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 2006; 20: 1331–1342.
- 30Bornstein S, White R, Malkoski S, et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest 2009; 119: 3408–3419.
- 31Myers JN, Holsinger FC, Jasser SA, Bekele BN, Fidler IJ. An orthotopic nude mouse model of oral tongue squamous cell carcinoma. Clin Cancer Res 2002; 8: 293–298.
- 32O'Malley BW Jr, Cope KA, Johnson CS, Schwartz MR. A new immunocompetent murine model for oral cancer. Arch Otolaryngol Head Neck Surg 1997; 123: 20–24.
- 33Vahle AK, Kerem A, Oztürk E, Bankfalvi A, Lang S, Brandau S. Optimization of an orthotopic murine model of head and neck squamous cell carcinoma in fully immunocompetent mice—role of toll-like-receptor 4 expressed on host cells. Cancer Lett 2012; 317: 199–206.
- 34Reddy NP, Miyamoto S, Araki K, et al. A novel orthotopic mouse model of head and neck cancer with molecular imaging. Laryngoscope 2011; 121: 1202–1207.
- 35Pla M, Mahouy G. The SCID mouse. Nouv Rev Fr Hematol 1991; 33: 489–491.
- 36Giovanella BC, Fogh J. The nude mouse in cancer research. Adv Cancer Res 1985; 44: 69–120.
- 37Pelleitier M, Montplaisir S. The nude mouse: a model of deficient T-cell function. Methods Achiev Exp Pathol 1975; 7: 149–166.
- 38Spector JG, Sessions DG, Haughey BH, et al. Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx. Laryngoscope 2001; 111: 1079–1087.
- 39Sanguineti G, Califano J, Stafford E, et al. Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2009; 74: 1356–1364.
- 40Pereira MC, Oliveira DT, Landman G, Kowalski LP. Histologic subtypes of oral squamous cell carcinoma: prognostic relevance. J Can Dent Assoc 2007; 73: 339–344.
- 41Woolgar JA, Triantafyllou A. Pitfalls and procedures in the histopathological diagnosis of oral and oropharyngeal squamous cell carcinoma and a review of the role of pathology in prognosis. Oral Oncol 2009; 45: 361–385.
- 42Ahmad A, Hart IR. Mechanisms of metastasis. Crit Rev Oncol Hematol 1997; 26: 163–173.
- 43Nathanson SD. Insights into the mechanisms of lymph node metastasis. Cancer 2003; 98: 413–423.
- 44Hoshida T, Isaka N, Hagendoorn J, et al. 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 2006; 66: 8065–8075.
- 45Bogenrieder T, Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 2003; 22: 6524–6536.
- 46Kawada K, Taketo MM. Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res 2011; 71: 1214–1218.
- 47Swartz MA, Lund AW. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer 2012; 12: 210–219.