Maxillofacial Plastic and Reconstructive Surgery

  • 제30권6호
  • /
  • Pages.529-539
  • /
  • 2008
  • /
  • 2288-8101(pISSN)
  • /
  • 2288-8586(eISSN)
대한악안면성형재건외과학회 (Korean Association of Maxillofacial Plastic and Reconstructive Surgeons)
권호 표지

구강 편평상피세포암 동위종양 모델에서 전이관련 인자의 발현

EXPRESSIONS OF METASTASIS-RELATED FACTORS IN ORTHOTOPIC TUMOR MODELS OF ORAL SQUAMOUS CELL CARCINOMA

  • 박영욱 (강릉대학교 치과대학 구강악안면외과학교실) ;
  • 이종원 (강릉대학교 치과대학 구강악안면외과학교실) ;
  • 김소희 (강릉대학교 치과대학 약리학교실)
  • Park, Young-Wook (Department of Oral and Maxillofacial Surgery, College of Dentistry, Kangnung National University) ;
  • Lee, Jong-Won (Department of Oral and Maxillofacial Surgery, College of Dentistry, Kangnung National University) ;
  • Kim, So-Hee (Department of Pharmacology, College of Dentistry, Kangnung National University)
  • 발행 : 2008.11.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background and Purpose : Oral squamous cell carcinoma (OSCC) is one of the most aggressive tumors of the head and neck area. OSCC is known to preferentially metastasize via lymphatic system, and resulting cervical lymph node metastasis is the most reliable of treatment failure. But the biological mechanism of the regional nodal metastasis is not clear. So, we determined metastasis-related factors in orthotopic nude mouse models of OSCC. Experimental Design : Two cell lines-KB and YD-10B cells, established from human oral mucosal squamous cell carcinoma, were xenografted into the tissue space of athymic murine mouth floor. The mice were followed for tumor development and growth, the murine tumors were examined histopathologically for local invasion or regional or distant metastasis. Finally, we performed immunohistochemical assays with antiepithelial growth factor (EGF), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), and anti-vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-2, phosphorylated VEGFR-2/3 (pVEGFR-2/3) antibodies. We also determined the microvessel density. Results : Transplantation of human OSCC tumor cells into the mouth floor successfully resulted in the formation of orthotopic tumors. KB cell line showed significantly higher tumor proliferation and higher nodal metastatic potential than YD-10B cell line. Furthermore, immunohistochemical staining demonstrated higher expression of EGFR/pEGFR, VEGF, and pVEGFR-2/3 as well as higher microvessel density in KB murine tumors than in YD-10B murine tumors. Conclusion : An orthotopic model of OSCC in athymic mice was established which copies the cervical lymph nodal metastasis of human OSCC. Our mouth floor model should facillitate the understanding of the molecular pathogenesis of cervical nodal metastasis of OSCC.

키워드

참고문헌

  1. Rodrigues VC, Moss SM, Tuomainen H : Oral cancer in the UK: To screen or not to screen. Oral Oncol 34 : 454, 1998 https://doi.org/10.1016/S1368-8375(98)00052-9
  2. Parkin DM, Pisani P, Ferlay J : Global cancer statistics. CA. Cancer J Clinicians 49 : 33, 1999 https://doi.org/10.3322/canjclin.49.1.33
  3. Lydiatt DD, Robbins KT, Byers RM et al : Treatment of stage I and II oral tongue cancer. Head Neck 15 : 308, 1993 https://doi.org/10.1002/hed.2880150407
  4. Silverman S Jr : Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the challenge. J Am Dent Assoc 132(Suppl) : 7S, 2001 https://doi.org/10.14219/jada.archive.2001.0382
  5. Grandi C, Alloisio M, Moglia D et al : Prognostic significance of lymphatic spread in head and neck carcinomas: Therapeutic implications. Head Neck Surg 8 : 67, 1985 https://doi.org/10.1002/hed.2890080202
  6. Sticht C, Freier K, Knopfle K et al : Activation of MAP kinases signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma (OSCC). Neoplasia 10 : 462, 2008 https://doi.org/10.1593/neo.08164
  7. Ho CM, Lam KH, Wei W et al : Occult lymph node metastasis in small oral tongue cancers. Head Neck 14 : 359, 1992 https://doi.org/10.1002/hed.2880140504
  8. Sano D, Myers JN : Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev 26 : 645, 2007 https://doi.org/10.1007/s10555-007-9082-y
  9. Cochran AJ, Morton DL : Management of the ragional lymph nodes in patients with cutaneous malignant melanoma. World J Surg 16 : 214, 1992 https://doi.org/10.1007/BF02071523
  10. 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 11 : 1963, 2005 https://doi.org/10.1158/1078-0432.CCR-04-1665
  11. Yigitbasi OG, Younes MN, Doan D et al : Tumor cell and endothelial cell therapy of oral cancer by dual tyrosine kinase receptor blockade. Cancer Res 64 : 7977, 2004 https://doi.org/10.1158/0008-5472.CAN-04-1477
  12. Park YW, In YS : Immunohistochemical assays for the expression of angiogenic signaling molecules and microvessel density in adenoid cystic carcinomas of human salivary glands. J Kor Assoc Oral Maxillofac Surg 32 : 530, 2006
  13. Hannen EJ, Riediger D : The quantification of angiogenesis in relation to metastasis in oral cancer: a review. Int J Oral Maxillofac Surg 33(1) : 2, 2004 https://doi.org/10.1054/ijom.2003.0433
  14. Myers JN, Holsinger FC, Jasser SA et al : An orthotopic nude mouse model of oral tongue squamous cell carcinoma. Clin Cancer Res 8 : 293, 2002
  15. Kim S, Park YW, Schiff BA et al : An orthotopic model of anaplastic thyroid carcinoma in athymic nude mice. Clin Cancer Res 8 : 293, 2002
  16. Park YW, Chung SH : An experimental study for establishment of orthotopic salivary tumor models in mice. J Kor Oral Maxillofac Surg 33(2) : 81, 2007
  17. Kowalski LP, Medina JE : Nodal metastasis: predictive factors. Otolaryngol Clin North Am. 31 : 621, 1998 https://doi.org/10.1016/S0030-6665(05)70076-1
  18. Maual SM, Luukkaa M, Grenman R et al : Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 63 : 1920, 2003
  19. Sleeman JP : The lymph node as a bridgehead in the metastatic dissemination of tumours. Recent Results Cancer Res 157 : 55, 2000
  20. Fidler IJ, Ellis LM : The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79 : 185, 1994 https://doi.org/10.1016/0092-8674(94)90187-2
  21. Neufeld G, Cohen T, Gitay-Goren H : Similarities and differences between the vascular endothelial growth factor (VEGF) splice variants. Cancer Metastasis Rev 15 : 153, 1996 https://doi.org/10.1007/BF00437467
  22. Stacker SA, Williams RA, Achen MG : Lymphangiogenic growth factors as markers of tumor metastasis. APMIS 112 : 539, 2004 https://doi.org/10.1111/j.1600-0463.2004.apm11207-0812.x
  23. Mustonen T, Alitalo K : Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol 129(4) : 895, 1995 https://doi.org/10.1083/jcb.129.4.895
  24. Rajesh V, David S, Jeffery D et al : Expression of vascular endothelial growth factor receptors on tumor cells in head and neck squamous cell carcinoma. Arch Otolaryn Head Neck Surg 129 : 882, 2003 https://doi.org/10.1001/archotol.129.8.882
  25. Folkman J : Angiogenesis in cencer, vascualr, rheumatoid, and other disease. Nature Med 1 : 27, 1995 https://doi.org/10.1038/nm0195-27
  26. Van Trappen PO, Steele D, Lowe DG et al : Expression of vascular endothelial growth factor (VEGF)-C and VEGFD, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 201 : 544, 2003 https://doi.org/10.1002/path.1467
  27. Shayan R, Achen MG, Stacker SA : Lymphatic vessels in cancer metastasis: bridging the gaps. Carcinogenesis 27(9) : 1729, 2006 https://doi.org/10.1093/carcin/bgl031
  28. Breiteneder-Geleff S, Soleiman A, Kowalski H et al : Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154 : 385, 1999 https://doi.org/10.1016/S0002-9440(10)65285-6
  29. Ohno F, Nakanishi 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 36 : 281, 2001
  30. Moriyama M, Kumagai S, Kawashiri K et al : Immunohistochemical study of tumour angiogenesis in oral squamous cell carcinoma. Oral Oncol 33(5) : 369, 1997 https://doi.org/10.1016/S1368-8375(97)00025-0
  31. Ullrich A, Schlessinger J : Signal transduction by receptors with tyrosine kinase activity. Cell 61 : 203, 1990 https://doi.org/10.1016/0092-8674(90)90801-K
  32. Abu-Ali S, Fotovati A, Shirasuna K : Tyrosine-kinase inhibition results in EGFR clustering at focal adhesions and consequent exocytosis in uPAR down-regulated cells of head and neck cancers. Mol Cancer 7 : 47, 2008 https://doi.org/10.1186/1476-4598-7-47
  33. Magkou C, Nakopoulou L, Zoubouli C et al : Expression of the epidermal growth factor receptor (EGFR) and the phosphorylated EGFR in invasive breast carcinomas. Breast Cancer Res 10(3) : R49, 2007
  34. Ang KK, Berkey BA, Tu X et al : Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62 : 7350, 2002
  35. Bei R, Budillon A, Masuelli L et al : Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients. Journal of Pathology, 204 : 317, 2004 https://doi.org/10.1002/path.1642