타액선 종양에서 혈관형성 인자의 발현에 관한 면역조직화학적 비교 연구

COMPARATIVE IMMUNOHISTOCHEMICAL ASSAYS FOR THE EXPRESSION OF ANGIOGENIC FACTORS IN TUMORS OF HUMAN SALIVARY GLANDS

  • 인연수 (강릉대학교 치과대학 구강악안면외과학교실) ;
  • 김성민 (강릉대학교 치과대학 구강악안면외과학교실) ;
  • 박영욱 (강릉대학교 치과대학 구강악안면외과학교실)
  • In, Yeon-Soo (Department of Oral and Maxillofacial Surgery, College of Dentistry, Kangnung National University) ;
  • Kim, Soung-Min (Department of Oral and Maxillofacial Surgery, College of Dentistry, Kangnung National University) ;
  • Park, Young-Wook (Department of Oral and Maxillofacial Surgery, College of Dentistry, Kangnung National University)
  • 발행 : 2007.01.31

초록

Hallmarks of clinical behaviors of adenoid cystic carcinoma(ACC) of salivary glands are the delayed onset of vascular metastasis and poor responses to classical chemotherapeutic agents. Poor prognoses from salivary ACC are caused by lung metastases that are resistant to conventional therapy. Therefore, cellular and molecular characteristics that influence the dissemination of metastatic cells are important for the design of more effective treatment of salivary ACC. Tumor angiogenesis has been known to be essential for the distant metastasis of malignant cells. So, we determined expressions of angiogenic proteins in benign (pleomorphic adenoma) and malignant (ACC, mucoepidermoid carcinoma) tumors of salivary glands and compared each other and to those in oral squamous cell carcinoma. Using surgical specimens, we performed immunohistochemical assays with anti-vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), phosphorylated VEGFR-2 (pVEGFR-2), matrix metalloproteinase (MMP)-9, and interleukin (IL)-8 antibodies. Most angiogenic factors were overexpressed in malignant salivary tumors than in pleomorphic adenoma which is benign nature. Moreover, ACC demonstrated more expression of VEGFR-2 than that of squamous cell carcinoma which used as control. Conclusively, these data show those angiogenic factors produced by salivary gland tumors may affect the propagation and metastasis of malignant cells of salivary tumors, and could be used as biomarkers for the malignant transformation of salivary gland tumors. Prospectively, although further studies will be needed, these biomarkers related to angiogenesis can be molecular targets for the therapy of salivary ACC, which has propensity for delayed vascular metastasis.

키워드

참고문헌

  1. Park YW : Celluar and molecular characterization of adenoid cyctic carcinoma of the salivary glands. J Kor Assoc Of Maxillofac Plast And Reconstr Surg 27(2) : 110, 2005
  2. Son CW, Kim KW, Kim CH : Study on Expression of gly-cosaminoglycan in adenoid cystic carcinoma. J Kor Oral Maxillofac Surg 30 : 271, 2004
  3. Zhang J, Peng B, Chen X : Expressions of Nuclear Factor KB, Inducible Nitric Oxide Synthase, and Vascular Endothelial Growth Factor in Adenoid Cystic Carcinoma of Salivary Glands : Correlations with the Angiogenesis and Clinical Outcome. Clin Cancer Res 11(20) : 7334, 2005 https://doi.org/10.1158/1078-0432.CCR-05-0241
  4. Ishibashi H, Shiratuchi T, Nakagawa K et al : Hypoxia-induced angiogenesis of cultured human salivary gland carcinoma cells enhances vascular endothelial growth factor production and basic fibroblast growth factor release. Oral Oncol 37 : 77, 2001 https://doi.org/10.1016/S1368-8375(00)00062-2
  5. Lloyd RV, Vidal S, Horvath E et al : Angiogenesis in normal and neoplastic pituitary tissues. Microsc ResTech 60 : 244, 2003 https://doi.org/10.1002/jemt.10263
  6. Airoldi M, Fornari G, Pedani F et al : Paclitaxel and car-boplatin for recurrent salivary gland malignancies. Anticancer Res 20(5C) : 3781, 2000
  7. Masabumi S : Differential Roles of Vascular Endothelial Growth Factor Receptor-1 and Receptor-2 in Angiogenesis. J Biochem Mol Biol Vol. 39, No. 5 : 2006. p.469 https://doi.org/10.5483/BMBRep.2006.39.5.469
  8. Nagel H , Laskawi R ,Wahlers A et al : Expression of matrix metalloproteinases and their tissue inhibitors TIMP-1, -2, and malignant tumours of the salivary. Histopathol 44 : 2004. p.222231 https://doi.org/10.1111/j.0309-0167.2004.01814.x
  9. Gomez DE, Alonso DF, Yoshiji H et al : Tissue inhibitors of metalloproteinases : structure, regulation and biological functions. Eur J Cell Biol 74(2) : 111, 1997
  10. Dano K, Romer J, Nielsen BS et al : Cancer invasion and tissue remodeling cooperation of protease systems and cell types. APMIS 107(1) : 120, 1999 https://doi.org/10.1111/j.1699-0463.1999.tb01534.x
  11. Shiozawa J, Ito M, Nakayama T : Expression of matrix metalloproteinase-1 in human colorectal carcinoma. Mod Pathol 13(9) : 925, 2000 https://doi.org/10.1038/modpathol.3880169
  12. Hebert CA, Baker JB : Interleukin-8 : A review. Cancer Invest 11(6) : 743, 1993 https://doi.org/10.3109/07357909309046949
  13. Ferrer FA, Miller LJ, Andrawis RI et al : Angiogenesis and prostate cancer: in vivo and in vitro expression of angiogenesis factors by prostate cancer cells. Urology 51(1) : 161, 1998
  14. Koch AE, Polverini PJ, Kunkel SL et al : Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089) : 1798, 1992 https://doi.org/10.1126/science.1281554
  15. Sauter ER, Nesbit M, Watson JC et al : Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinoma of the head and neck, Clin Cancer Res 5 : 775, 1999
  16. Fox SB : Tumor angiogenesis and prognosis. Histopathol 30 : 294, 1997 https://doi.org/10.1046/j.1365-2559.1997.d01-606.x
  17. Dickinson AJ, Fox SB, Persad J : Quantification of angio-genesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74 : 762, 1994 https://doi.org/10.1111/j.1464-410X.1994.tb07122.x
  18. Jaeger TM, Weidner N, Chew K : Tumor angiogenesis correlates with lymph node metastasis in invasive bladder cancer. J Urol 154 : 69, 1995 https://doi.org/10.1016/S0022-5347(01)67230-6
  19. Takahashi Y, Kitadai Y, Bucana CD : Expression of vascular endothelial cell growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55 : 3964, 1995
  20. Tanigawa N, Amaya H, Matsumura M : Extent of tumor vascularization correlates with the prognosis and hematogenous metastasis in gastric carcinomas. Cancer Res 56 : 2671, 1996
  21. Gasparini G, Harris AL : Clinical importance of the determination of tumor angiogenesis in breast carcinoma : Much more than a new prognostic tool. J Clin Oncol 13 : 765, 1995 https://doi.org/10.1200/JCO.1995.13.3.765
  22. Park YW, In YS : Immunohistochemical assays for the expression of angiogenic signaling molecules and microves-sel density in adenoid cystic carcinomas of human salivary glands. J Kor Oral Maxillofac Surg 32(6) : 530, 2006
  23. Myoung H, Kim YY, Choi SM : Immunohistochemical study of the vascular endothelial Growth factor (vegf) expression in genistein treated Hamster buccal pouch oral carcinoma model. J Kor Oral Maxillofac Surg 28 : 147, 2002
  24. O-Charoenrat P, Rhys-Evans P, Eccles S : Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 92 : 556, 2001 https://doi.org/10.1002/1097-0142(20010801)92:3<556::AID-CNCR1355>3.0.CO;2-Q
  25. Verheul HM, Panigrahy D, Yuan J et al : Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer 79 : 114, 1999 https://doi.org/10.1038/sj.bjc.6690020
  26. Neuchrist C, Quint C, Pammer A et al : Vascular endothelial growth factor (VEGF) and microvessel density in squamous cell carcinomas of the larynx: an immunohis-tochemical study. Acta Otolaryngol 119(6) : 732, 1999 https://doi.org/10.1080/00016489950180711
  27. Obermair A, Kohlberger P, Bancher-Todesca D et al : Influence of microvessel density and vascular permeability factor/vascular endothelial growth factor expression on prognosis in vulvar cancer. Gynecol Oncol 63(2) : 204, 1996 https://doi.org/10.1006/gyno.1996.0307
  28. Kleespies A, Bruns CJ, Jauch KW : Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies. Onkologie 28(5) : 281, 2005 https://doi.org/10.1159/000085198
  29. Petruzzelli GJ, Benefield J, Taitz AD et al : Heparin-bind-ing growth factors derived from head and neck squamous cell carcinomas induce endothelial cell proliferation. Head Neck 19(7) : 576, 1997 https://doi.org/10.1002/(SICI)1097-0347(199710)19:7<576::AID-HED3>3.0.CO;2-4
  30. Moriyama M, Kumagai S, Kawashiri S 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. Richards BL, Eisma RJ, Spiro JD et al : Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am Surg 174(5) : 507, 1997 https://doi.org/10.1016/S0002-9610(97)00165-7
  32. Eisma RJ, Spiro JD, Kreutzer DL : Role of angiogenic factors : coexpression of interleukin-8 and vascular endothe-lial growth factor in patients with head and neck squamous carcinoma. Laryngoscope 109(5) : 687, 1999 https://doi.org/10.1097/00005537-199905000-00002
  33. Sedivy R, Beck-Mannagetta J, Haverkampf C et al : Expression of vascular engothelial growth factor-C correlates with the lymphatic microvessel density and the nodal status in oral squamous cell cancer. J Oral Pathol Med 32 : 455, 2003 https://doi.org/10.1034/j.1600-0714.2003.00168.x
  34. Leedy DA, Trune DR, Kronz JD et al : Tumor angiogene-sis, the p53 antigen, and cervical metastasis in squamous cell carcinoma of the tongue. Otolaryngol Head Neck Surg 111 : 417, 1994 https://doi.org/10.1177/019459989411100405
  35. Williams JK, Carlson GW, Cohen C et al : Tumor angio-genesis as a prognostic factor in oral cavity tumor. Am J Surg 168 : 373, 1994 https://doi.org/10.1016/S0002-9610(05)80079-0
  36. Pazouki S, Chisholm DM, Adi MM et al : The association between tumour progression and vascularity in the oral mucosa. J Pathol 183 : 39, 1997 https://doi.org/10.1002/(SICI)1096-9896(199709)183:1<39::AID-PATH1088>3.0.CO;2-L
  37. Sion-Vardy N, Fliss DM, Prinsloo I et al : Neoangiogenesis in squamous cell carcinoma of the larynx bio biological and prognostic associations. Pathol Res Pract 197(1) : 1, 2001 https://doi.org/10.1078/0344-0338-00001
  38. Shpitzer T, Chaimoff M, Gal R et al : Tumor angiogenesis as a prognostic factor in early oral tongue cancer. Arch Otolaryngol Head Neck Surg 122 : 865, 1996 https://doi.org/10.1001/archotol.1996.01890200055012
  39. Gasparini G, Weidner N, Maluta S et al : Intratumoral microvessel density and p53 protein : correlation with metastasis in head and neck carcinoma. Int J Cancer 55 : 739, 1993 https://doi.org/10.1002/ijc.2910550507
  40. Lim JJ, Kang S, Lee MR et al : Expression of vascular endothelial growth factor in salivary gland carcinomas and its relation to p53, ki-67 and prognosis. J Oral Pathol Med 32 : 552, 2003 https://doi.org/10.1034/j.1600-0714.2003.00145.x
  41. Lee GC, Myoung H, Lim SS: The clinicopathological study on the relation of microvessel density And aggressiveness in oral squamous cell carcinoma. J Kor Oral Maxillofac Surg 28 : 155, 2002