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Inhibition of Lymphatic Endothelial Growth Factor Receptor in a Murine Model of Oral Squamous Cell Carcinoma  

Kye, Jun-Young (Department of Oral and Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University)
Park, Young-Wook (Department of Oral and Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University)
Publication Information
Maxillofacial Plastic and Reconstructive Surgery / v.33, no.1, 2011 , pp. 1-9 More about this Journal
Abstract
Purpose: Tumor associated angiogenesis and/or lymphangiogenesis are known to be linked by VEGFR signaling pathways. These processes are regulated by several growth factors including VEGFR-2, VEGFR-3. E7080 is an orally active inhibitor of multiple tyrosine kinases including VEGFR-2, 3. Therefore, it was proposed that E7080 may inhibit angiogenesis and lymphangiogenesis. The aim of this study was to determine the effect of E7080 in a nude mouse model of OSCC. Methods: KB cells were xenografted into the submucosal tissue of the mouth floor of athymic mice. Seven days after the xenograft, the mice were randomized into 2 groups. E7080 were administered orally to the experimental group once per day. The mice were sacrificed 3 weeks after the treatment. The tumors were examined histopathologically. Immunohistochemical assays with anti- VEGF-C, VEGFR-2, VEGFR-3, phosphorylated VEGFR-2/3 (pVEGFR-2/3), and D2-40 antibodies were then performed. Results: The transplantation of human OSCC tumor cells into the mouth floor resulted in the formation of orthotopic tumors. The experimental (E7080 treatment) group showed a slowly increased tumor volume. Moreover, immunohistochemical staining demonstrated higher levels of VEGF-C, VEGFR-2, VEGFR-3, pVEGFR-2/3 and D2-40 expression in the control group than in the experimental group. Conclusion: These results suggest that E7080 may provide therapeutic benefits in OSCC.
Keywords
OSCC; Angiogenesis; Lymphangiogenesis; VEGFR; E7080;
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1 He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 2005;65:4739-46   DOI   ScienceOn
2 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med 1995;1:27-31.   DOI   ScienceOn
3 Neuchrist C, Erovic BM, Handisurya A, et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck 2003;25:464-74.   DOI   ScienceOn
4 Park YW, Kim SG, Kim SH, Kim HS, Kim MK. Gene expression for lymphangiogenic factors in oral mucosal squamous cell carcinoma. J Korean Acad Maxillofac Plast Reconst Surg 2009;31:453-60.
5 Van Trappen PO, Steele D, Lowe DG, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 2003;201:544-54.   DOI   ScienceOn
6 Escudier B, EisenT, StadlerWM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34.   DOI   ScienceOn
7 Joukov V, Sorsa T, Kumar V, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 1997;16:3898-911.   DOI   ScienceOn
8 Nakamura Y, Yasuoka H, Tsujimoto M, et al. Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res Treat 2005;91: 125-32.   DOI   ScienceOn
9 Tsurusaki T, Kanda S, Sakai H, et al. Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer 1999;80:309-13.   DOI
10 Yonemura Y, Endo Y, Fujita H, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res 1999;5:1823-9.
11 Niki T, Iba S, Tokunou M, Yamada T, Matsuno Y, Hirohashi S. Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res 2000;6:2431-9.
12 Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol 2008;26:535-41.   DOI   ScienceOn
13 Karpanen T, Egeblad M, Karkkainen MJ, et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001; 61:1786-90.
14 Roberts N, Kloos B, Cassella M, et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 2006;66:2650-7.   DOI   ScienceOn
15 Sticht C, Freier K, Knopfle K, et al. Activation of MAP kinase signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma (OSCC). Neoplasia 2008;10:462-70.   DOI
16 Willett CG, BoucherY, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145-7.   DOI   ScienceOn
17 Ho CM, Lam KH, Wei WI, Lau SK, Lam LK. Occult lymph node metastasis in small oral tongue cancers. Head Neck 1992;14:359-63.   DOI   ScienceOn
18 Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795-803.   DOI   ScienceOn
19 Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 2002;1:219-27.   DOI   ScienceOn
20 Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and plateletderived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16-24.   DOI   ScienceOn
21 Gershenwald JE, Fidler IJ. Cancer. Targeting lymphatic metastasis. Science 2002;296:1811-2.   DOI
22 Kupferman ME, Myers JN. Molecular biology of oral cavity squamous cell carcinoma. Otolaryngol Clin North Am 2006; 39:229-47.   DOI   ScienceOn
23 Silverman S Jr. Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the chalenge. J Am Dent Assoc 2001;132(Suppl):7S-11S.
24 Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2002;2:573-83.   DOI   ScienceOn
25 Park YW, Younes MN, Jasser SA, et al. AEE788, a dual tyrosine kinase receptor inhibitor, induces endothelial cell apoptosis in human cutaneous squamous cell carcinoma xenografts in nude mice. Clin Cancer Res 2005;11:1963-73.   DOI   ScienceOn
26 Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res 2005;11:8364-71.   DOI   ScienceOn
27 Ohno F, Nacknishi H, Abe A, et al. Regional difference in intratumoral lymphangiogenesis of oral squamous cell carcinomas evaluated by immunohistochemistry using D2-40 and podoplanin antibody: an analysis in comparison with angiogenesis. J Oral Pathol Med 2007;36:281-9.   DOI   ScienceOn
28 Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of VEGFR-2 and VEGFR-3 kinase. Clin Cancer Res 2008;14:5459-65.   DOI   ScienceOn
29 Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008;122:664-71.   DOI   ScienceOn
30 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.   DOI   ScienceOn
31 Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185-8.   DOI   ScienceOn
32 Stacker SA, Williams RA, Achen MG. Lymphangiogenic growth factors as markers of tumor metastasis. APMIS 2004; 112:539-49.   DOI   ScienceOn