IMMUNOHISTOCHEMICAL STUDY ON EXPRESSION OF LYMPHANGIOGENIC FACTORS IN ORAL CANCER

구강암에서 림프관형성 인자의 발현에 관한 면역조직화학적 연구

  • Park, Young-Wook (Department of Oral & Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University) ;
  • Kwon, Kwang-Jun (Department of Oral & Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University) ;
  • Lee, Jong-Won (Department of Oral & Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University)
  • 박영욱 (강릉원주대학교 치과대학 구강악안면외과학교실) ;
  • 권광준 (강릉원주대학교 치과대학 구강악안면외과학교실) ;
  • 이종원 (강릉원주대학교 치과대학 구강악안면외과학교실)
  • Received : 2009.12.28
  • Accepted : 2010.01.20
  • Published : 2010.01.29

Abstract

Background and Purpose: Vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 are involved in tumor lymphangiogenesis. Oral mucosal squamous cell carcinoma (OMSCC) preferentially metastasizes to cervical lymph nodes, so we investigated the expression and distribution of VEGFR-3 signaling proteins in OMSCC. Materials and Methods: Tissue samples of 18 OMSCC, 10 oral mucosal leukoplakia, and 3 normal oral mucosa were evaluated for expression of VEGF-C, VEGF-D, and VEGFR-3 by immunohistochemical staining. The presence of lymphatic vessels was determined using D2-40 staining, by which we also measured lymphatic vessel density (LVD). Results: 72% (13/18) and 56% (10/18) of tissue samples showed VEGF-C and VEGF-D immunopositivity in tumor cells and tumor-associated endothelial cells. VEGFR-3 was also expressed in most of OMSCC, which was up-regulated when compared with normal mucosa or with leukoplakia. Furthermore, LVD was higher in OMSCC than in leukoplakia. Conclusion: Taken together, our results suggest that autocrine activation of lymphatic endothelial cell via VEGFR-3 by VEGF-C and/or VEGF-D could be involved in progression of OMSCC. Therefore, VEGF-C/VEGFR-3 signaling pathway can be a molecular target for anti-metastatic therapy in OMSCC.

Keywords

References

  1. Pepper MS : Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 7 : 462, 2001.
  2. Saharinen P, Tammela T, Karkkainen MJ et a1 : Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immuno 125 : 387, 2004.
  3. Achen MG, Stacker SA : Tumor lymphangiogenesis and metastatic spread - New players begin to emerge. Int J Cancer 119 : 1755, 2006. https://doi.org/10.1002/ijc.21899
  4. Zeng Y, Opeskin K, Baldwin ME et al : Expression of cascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clinical Cancer Reserch 10 : 5137, 2004.
  5. Stacker SA, Achen MG, Jussila L et al : Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2 : 573, 2002. https://doi.org/10.1038/nrc863
  6. Brychtova S, Bezdekova M, Brychta T et al : The role of vascular endothelial growth factors and their receptors in malignant melanomas. Neoplasma 55(4) : 273, 2008.
  7. Tanaka K, Miki C, Wakuda R et al : Circulating level of hepatocyte growth factor as a useful tumor marker in patient with early-stage gastric carcinoma. Scand L Gastroenterol 39 : 754. 2004. https://doi.org/10.1080/00365520410005973
  8. Chang LK, Garcia-Cardena G, Farnebo F et al : Dosedependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 101 : 11658, 2004. https://doi.org/10.1073/pnas.0404272101
  9. Stiligoi C, de Luca A, Cascone I et al : Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int J Cancer 103 : 466, 2003. https://doi.org/10.1002/ijc.10851
  10. Cao R, Bjorndahl MA. Religa P et al : PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6 : 333, 2004. https://doi.org/10.1016/j.ccr.2004.08.034
  11. Bjorndahl M, Cao R, Nissen LJ et al : Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 102 : 15593, 2005. https://doi.org/10.1073/pnas.0507865102
  12. O-charoenrat P, Rhys-Evans P, Eccles SA : 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
  13. 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 Jun:25(6): 464-474. https://doi.org/10.1002/hed.10235
  14. Sedivy R. Mannagetta JB. Battistutti W et al : Exression of vascular endothelial growth factor-C correlates with the lymphatic microvessel density and the nodal status un oral squamous cell cancer. J Oral Pathol Med. 2003 Oct 15: 146(2) 455-460.
  15. Shintani S. Li C, Ishikawa T et al : Expression of vascular endothelial growth factor A, B, C, and D in oral squamous cell carcinoma. Oral Oncol 40 : 13. 2004.
  16. Miyahara M. Tanuma JI. Sugihara K et al : Tumor Iymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Cancer. 2007 Sep 15:110(6): 1287-1294. https://doi.org/10.1002/cncr.22900
  17. 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
  18. Park YW. Kim SG. Kim SH et al : Gene expression for lymphangiogenic factors in oral mucosal squamous cell carcinoma. J Kor Acad Maxillofac Plast Reconst Surg 31 (6) : 453, 2009.
  19. 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
  20. Witte D, Thomas A, Ali N et al : Expression of the vascular endothelial growth factor receptor-3(VEGFR-3) and its ligand VEGF-C in human colorectal adenocacinama. Anticancer Res 22(3) : 1463, 2002.
  21. 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 65 : 4739, 2005. https://doi.org/10.1158/0008-5472.CAN-04-4576
  22. Schoppmann SF, Eimer P, Stockl J et al : Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Amer J of Pathol 161(3) : 947, 2002. https://doi.org/10.1016/S0002-9440(10)64255-1
  23. Gombos Z, Xu X, Chu CS et al : Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res 11 : 8364, 2005. https://doi.org/10.1158/1078-0432.CCR-05-1238
  24. Weidner N, Semple J, Welch W et al : Tumor angiogenesis and metastasis-correlation in invasive breast cancer. N Engl J Med 324 : 1, 1991. https://doi.org/10.1056/NEJM199101033240101
  25. Valencak J, Heere-Ress E, Kopp T et al : Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma. Eur J Cancer 40 : 358. 2004. https://doi.org/10.1016/j.ejca.2003.09.009
  26. Ohno F, Nacknishi H, Abe A et al : Regional difference in intratumoral Iymphangiogenesis of oral squamous cell carcinoma evaluated by immunohistochemistry using D2-40 and podoplanin antibody: an analysis in comparison with angiogenesis. J Oral Pathol Med 36 : 281, 2007. https://doi.org/10.1111/j.1600-0714.2007.00529.x
  27. Neuchrist C. Erovic BM, Handisurya A et al : Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Expression in Squamous Cell Carcinomas of the Head and Neck. Laryngoscope 111 : 1834, 2001. https://doi.org/10.1097/00005537-200110000-00031
  28. Masood R, Cai J, Zheng T et al : Vascular endothelial growth factor(VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood 98 : 1904, 2001. https://doi.org/10.1182/blood.V98.6.1904
  29. Wey JS, Stoeltzing O, Ellis LM : Vascular endothelial growth factor receptors: expression and function in solid tumors. Clin Adv Hematol Onco 2(1) : 37, 2004.
  30. Yang AD, Camp ER, Fan F et al : Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transtion in human pancreatic carcinoma cells. Cancer Res 66 : 46, 2006. https://doi.org/10.1158/0008-5472.CAN-05-3086
  31. Moser C. Lang SA, Stoeltzing O : The direct effects of anti-vascular endothelial growth factor therapy on tumor cells. Clin Colorectal Cancer 6(8) : 564, 2007. https://doi.org/10.3816/CCC.2007.n.023
  32. Valtola R, Salven P, Heikkila Pet al : VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J PathoI 154(5) : 1381, 1999. https://doi.org/10.1016/S0002-9440(10)65392-8
  33. Stacker SA, Caesar C, Baldwin ME et al : VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7 : 186, 2001. https://doi.org/10.1038/84635
  34. Tang RF, Itakura J. Aikawa T et al : Overexpression of Iymphangiogenic growth factor VEGF-C in human pancreatic cancer. Pancreas 22(3) : 285, 2001. https://doi.org/10.1097/00006676-200104000-00010
  35. Gee MF, Tsuchida R, Eichler-Jonsson C et al : Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with alltrans-retinoic acid. Oncogene 24(54) : 8025, 2005. https://doi.org/10.1038/sj.onc.1208939
  36. Su JL. Yen CJ, Chen PS et al : The role of the VEGFC/VEGFR-3 axis in cancer progression. Br J Cancer 96 : 541, 2007. https://doi.org/10.1038/sj.bjc.6603487