Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
권호 표지

Clinical Significance of VEGF-C and COX-2 Expression in Gastric Carcinoma with Submucosal Invasion

점막하 침윤 조기위암 환자에서 VEGF-C와 COX-2 발현의 임상적 의의

  • Cho, Yun-Jung (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Lee, Jung-Uee (Department of Hospital Pathology, The Catholic University of Korea College of Medicine) ;
  • Lee, Kwan-Ju (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Park, Cho-Hyun (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Park, Seung-Man (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Jeon, Hae-Myung (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Ahn, Chang-Joon (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Kim, Jeong-Goo (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Lee, Dong-Ho (Department of Surgery, The Catholic University of Korea College of Medicine) ;
  • Lee, Sang-Chul (Department of Surgery, The Catholic University of Korea College of Medicine)
  • 조윤정 (가톨릭대학교 의과대학 외과학교실) ;
  • 이정의 (가톨릭대학교 의과대학 병원병리학교실) ;
  • 이관주 (가톨릭대학교 의과대학 외과학교실) ;
  • 박조현 (가톨릭대학교 의과대학 외과학교실) ;
  • 박승만 (가톨릭대학교 의과대학 외과학교실) ;
  • 전해명 (가톨릭대학교 의과대학 외과학교실) ;
  • 안창준 (가톨릭대학교 의과대학 외과학교실) ;
  • 김정구 (가톨릭대학교 의과대학 외과학교실) ;
  • 이동호 (가톨릭대학교 의과대학 외과학교실) ;
  • 이상철 (가톨릭대학교 의과대학 외과학교실)
  • Published : 2009.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Lymph node metastasis is an important factor in determining prognosis and therapeutic options for early gastric cancer (EGC) patients. Vascular endothelial growth factor (VEGF)-C and D are known as lymphangiogenic factors, and cyclooxygenase (COX)-2 is thought to play a role in lymph node metastasis in gastric carcinoma. This study was designed to determine whether the expression of VEGF-C, VEGF-D, and COX-2 is associated with clinicopathologic factors, especially lymph node metastasis in EGCs invading the submucosa. Materials and Methods: Tissue samples were obtained from 85 Patients undergoing standard gastrectomy with lymph node dissection between 1991 and 2007 in the Department of Surgery of Daejeon St. Mary's Hospital in Daejeon, Korea. All patients were diagnosed with gastric cancers and submucosal invasion. We examined the expression of VEGF-C, VEGF-D, and COX-2 using immunohistochemical methods. Results: Of the 85 patients, 16 (18.8%) had lymph node metastasis. VEGF-C, VEGF-D, and COX-2 were positively expressed in 34.1% (29/85), 22.3% (19/85), and 37.6% (32/85) of the patients. VEGF-C and COX-2 expression was significantly correlated with lymph node metastasis (P<0.05). A positive correlation existed between VEGF-C and COX-2 expression (P< 0.001). Conclusion: VEGF-C and COX-2 expression is associated with lymph node metastasis in gastric cancer with submucosal invasion. VEGF-C and COX-2 may thus be predictive markers for lymph node metastasis in EGC patients with submucosal invasion.

목적: Vascular endothelial growth factor (VEGF)-C와 -D 및 Cyclooxygenase (COX)-2는 위암에서 림프절 전이와 연관이 있다고 알려져 있다. 이에 저자들은 점막하 침윤 조기위암에서 VEGF-C와 -D 및 COX-2의 발현과 림프절 전이 등을 포함하는 다양한 임상병리학적 인자와의 관련성을 알아 보고자 하였다. 대상 및 방법: 1991년 1월부터 2007년 10월까지 본원에서 점막하 침윤 조기위암으로 수술을 시행 받은 85명의 환자를 대상으로 VEGF-C, -D 및 COX-2와 VEGF-C에 대한 면역 조직화학 염색을 시행하였다. 염색의 결과에 따라 환자군을 나누어 다양한 임상병리학적 인자와의 연관성을 조사하였고, 또 이 세 가지 인자들 상호 간의 연관 관계를 분석하였다. 결과: 전체 85명의 환자 중 16명이 림프절 전이가 있었다(18.8%). VEGF-C는 34.1% VEGF-D는 22.3% 그리고 COX-2는 37.6%가 양성으로 판정되었다. 이 중 VEGF-C와 COX-2 모두 림프절 전이와 유의한 상관관계를 보였고(P<0.001, P=0.023). VEGF-D와 연관성을 보이는 인자는 확인하지 못하였다. 또 VEGF-C와 COX-2의 발현은 밀접한 상관관계를 보였다(P=0.001). 결론: 점막하 침윤 조기위암에서 VEGF-C와 COX-2는 림프절 전이와 연관이 있고, 따라서 이 두 인자가 점막하 침윤 조기위암의 림프절 전이를 예측하는 인자로서의 가능성이 있다고 할 수 있겠다.

Keywords

References

  1. Noguchi Y, Yoshikawa T, Tsuburaya A, Motohashi H, Karpeh MS, Brennan MF. Is gastric carcinoma different between Japan and the United States? Cancer 2000;89:2237-2246. https://doi.org/10.1002/1097-0142(20001201)89:11<2237::AID-CNCR12>3.0.CO;2-9
  2. Katai H, Sano T. Early gastric cancer: concepts, diagnosis, and management. Int J Clin Oncol 2005;10:375-383. https://doi.org/10.1007/s10147-005-0534-5
  3. Ono H. Early gastric cancer: diagnosis, pathology, treatment techniques and treatment outcomes. Eur J Gastroenterol Hepatol 2006;18:863-866. https://doi.org/10.1097/00042737-200608000-00009
  4. Kitagawa Y, Kitano S, Kubota T, Kumai K, Otani Y, Saikawa Y, Yoshida M, Kitajima M. Minimally invasive surgery for gastric cancer--toward a confluence of two major streams: a review. Gastric Cancer 2005;8:103-110. https://doi.org/10.1007/s10120-005-0326-7
  5. Katai H. Function-preserving surgery for gastric cancer. Int J Clin Oncol 2006;11:357-366. https://doi.org/10.1007/s10147-006-0613-2
  6. Sano T, Hollowood A. Early gastric cancer: diagnosis and less invasive treatments. Scand J Surg 2006;95:249-255. https://doi.org/10.1177/145749690609500407
  7. Gotoda T. Endoscopic resection of early gastric cancer. Gastric Cancer 2007;10:1-11. https://doi.org/10.1007/s10120-006-0408-1
  8. Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T, Kato Y. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219-225. https://doi.org/10.1007/PL00011720
  9. Ohashi S, Okamura S, Urano F, Maeda M. Clinicopathological variables associated with lymph node metastasis in submucosal invasive gastric cancer. Gastric Cancer 2007;10:241-250. https://doi.org/10.1007/s10120-007-0442-7
  10. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 2002;1:219-227. https://doi.org/10.1016/S1535-6108(02)00051-X
  11. He Y, Karpanen T, Alitalo K. Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta 2004;1654:3-12.
  12. Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, Chayama K. Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer 2002;38:1413-1419. https://doi.org/10.1016/S0959-8049(02)00106-5
  13. Duff SE, Li C, Jeziorska M, Kumar S, Saunders MP, Sherlock D, O'Dwyer ST, Jayson GC. Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy. Br J Cancer 2003;89:426-430. https://doi.org/10.1038/sj.bjc.6601145
  14. Joo YE, Rew JS, Seo YH, Choi SK, Kim YJ, Park CS, Kim SJ. Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer. J Clin Gastroenterol 2003;37:28-33. https://doi.org/10.1097/00004836-200307000-00009
  15. Saukkonen K, Nieminen O, van Rees B, Vilkki S, Harkonen M, Juhola M, Mecklin JP, Sipponen P, Ristimäki A. Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma. Clin Cancer Res 2001; 7:1923-1931.
  16. Mrena J, Wiksten JP, Thiel A, Kokkola A, Pohjola L, Lundin J, Nordling S, Ristimäki A, Haglund C. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 2005;11:7362-7368. https://doi.org/10.1158/1078-0432.CCR-05-0764
  17. Zhang J, Ji J, Yuan F, Zhu L, Yan C, Yu YY, Liu BY, Zhu ZG, Lin YZ. Cyclooxygenase-2 expression is associated with VEGF-C and lymph node metastases in gastric cancer patients. Biomed Pharmacother 2005;59(Suppl 2):285s-288s. https://doi.org/10.1016/S0753-3322(05)80047-2
  18. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma - 2nd English edition. Gastric Cancer 1998;1:10-24. https://doi.org/10.1007/PL00011681
  19. Ishikawa S, Togashi A, Inoue M, Honda S, Nozawa F, Toyama E, Miyanari N, Tabira Y, Baba H. Indications for EMR/ESD in cases of early gastric cancer: relationship between histological type, depth of wall invasion, and lymph node metastasis. Gastric Cancer 2007;10:35-38. https://doi.org/10.1007/s10120-006-0407-2
  20. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol 2004;25:387-395. https://doi.org/10.1016/j.it.2004.05.003
  21. Gao P, Zhou GY, Zhang QH, Su ZX, Zhang TG, Xiang L, Wang Y, Zhang SL, Mu K. Lymphangiogenesis in gastric carcinoma correlates with prognosis. J Pathol 2009;218:192-200. https://doi.org/10.1002/path.2523
  22. Onogawa S, Kitadai Y, Amioka T, Kodama M, Cho S, Kuroda T, Ochiumi T, Kimura S, Kuwai T, Tanaka S, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in early gastric carcinoma: correlation with clinicopathological parameters. Cancer Lett 2005;226:85-90. https://doi.org/10.1016/j.canlet.2004.12.030
  23. Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, Rio MC, Haglund C, Van Lanschot JJ, Offerhaus GJ, Ristimaki A. Cyclooxygenase-2 and gastric carcinogenesis. APMIS 2003;111:915-925. https://doi.org/10.1034/j.1600-0463.2003.1111001.x
  24. Fujimura T, Ohta T, Oyama K, Miyashita T, Miwa K. Cyclooxygenase- 2 (COX-2) in carcinogenesis and selective COX- 2 inhibitors for chemoprevention in gastrointestinal cancers. J Gastrointest Cancer 2007;38:78-82. https://doi.org/10.1007/s12029-008-9035-x
  25. Walther Z. COX-2 and angiogenesis in gastric cancer. J Clin Gastroenterol 2003;37:4-6. https://doi.org/10.1097/00004836-200307000-00003
  26. Da MX, Wu XT, Wang J, Guo TK, Zhao ZG, Luo T, Zhang MM, Qian K. Expression of cyclooxygenase-2 and vascular endothelial growth factor-C correlates with lymphangiogenesis and lymphatic invasion in human gastric cancer. Arch Med Res 2008;39:92-99. https://doi.org/10.1016/j.arcmed.2007.06.021
  27. Chun H, Kwon SJ, Paik SS, Song YS. Effects of cyclooxygenase- 2 expression on lympangiogenesis and lymph node metastasis in gastric cancer tissues. J Korean Gastric Cancer Assoc 2006;6:284-290. https://doi.org/10.5230/jkgca.2006.6.4.284
  28. Kwee RM, Kwee TC. Predicting lymph node status in early gastric cancer. Gastric Cancer 2008;11:134-148. https://doi.org/10.1007/s10120-008-0476-5