J Korean Med Sci.  2008 Aug;23(4):592-597. 10.3346/jkms.2008.23.4.592.

Correlation of Vascular Endothelial Growth Factor-D Expression and VEGFR-3-Positive Vessel Density with Lymph Node Metastasis in Gastric Carcinoma

Affiliations
  • 1Department of Internal Medicine, College of Medicine, Hanyang University, Seoul, Korea. jhcmd@hanyang.ac.kr
  • 2Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • 3Department of Surgery, College of Medicine, Hanyang University, Seoul, Korea.

Abstract

Lymph node metastasis is an important prognostic factor in gastric cancer. Vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that activates VEGF receptor (VEGFR)-3, a receptor expressed in the lymphatic endothelium. We investigated the clinical value of VEGF-D expression and VEGFR-3 positive vessel density in gastric carcinoma with regard to lymphangiogenesis. Immunohistochemical staining was used to determine the expression of VEGF-D and VEGFR- 3 in specimens from 104 cases of resected gastric cancer. VEGF-D expression was observed in 62.5% of the gastric cancers and in 9.6% of the non-neoplastic gastric tissue. The VEGFR-3-positive vessel density was significantly greater in the VEGFD positive group than the negative group. VEGF-D expression was significantly associated with lymph node metastasis, increased serum CEA levels, and the nonsignet ring cell type. The VEGFR-3-positive vessel density was correlated with tumor size, lymphatic invasion, and lymph node metastasis. The VEGF-D expression and high VEGFR-3-positive vessel density were significant poor prognostic factors for relapse-free survival. These results suggest that VEGF-D and VEGFR-3-positive vessel density are potential molecular markers that predict lymphatic involvement in gastric carcinoma.

Keyword

Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3; Stomach Neoplasms

MeSH Terms

Adult
Aged
Female
Humans
Immunohistochemistry
Lymphatic Metastasis
Male
Middle Aged
Prognosis
Stomach Neoplasms/*blood supply/chemistry/*pathology
Vascular Endothelial Growth Factor D/*analysis
Vascular Endothelial Growth Factor Receptor-3/*analysis

Figure

  • Fig. 1 Immunohistochemical staining of a gastric carcinoma. Each photograph shows representative tissue that is positive for VEGF-D (A) and VEGFR-3 (B) (×400).

  • Fig. 2 Correlation between VEGF-D expression and VEGFR-3-positive vessel density (FVD).

  • Fig. 3 Relapse-free survival of patients with gastric cancer according to VEGF-D expression (A) and VEGFR-3-positive vessel density (B).


Reference

1. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001. 7:186–191.
Article
2. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001. 20:672–682.
Article
3. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001. 7:192–198.
Article
4. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 1996. 15:290–298.
Article
5. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997. 276:1423–1425.
Article
6. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA. 1998. 95:548–553.
Article
7. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 2001. 20:1223–1231.
Article
8. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA. 1995. 92:3566–3570.
Article
9. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000. 60:203–212.
10. Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol. 2000. 156:1499–1504.
Article
11. White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, Murray JC. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 2002. 62:1669–1675.
12. Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K. Prognostic significance of vascular endothelial growth factor D in breast carcinoma with long-term follow-up. Clin Cancer Res. 2003. 9:716–721.
13. Kurahara H, Takao S, Maemura K, Shinchi H, Natsugoe S, Aikou T. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: its relationship to lymph node metastasis. Clin Cancer Res. 2004. 10:8413–8420.
14. Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Umemoto M, Sakamoto T, Sato S, Mizunuma H, Smith SK. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer. 2003. 88:237–244.
Article
15. Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Sakamoto A, Sakamoto T, Maruyama H, Sato S, Mizunuma H, Smith SK. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res. 2003. 9:1361–1369.
16. Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K. Flt-4-positive vessel density correlates with vascular endothelial growth factor-D expression, nodal status, and prognosis in breast cancer. Clin Cancer Res. 2003. 9:5313–5317.
17. Chen F, Takenaka K, Ogawa E, Yanagihara K, Otake Y, Wada H, Tanaka F. Flt-4-positive endothelial cell density and its clinical significance in non-small cell lung cancer. Clin Cancer Res. 2004. 10:8548–8553.
Article
18. Jüttner S, Wissmann C, Jöns T, Vieth M, Hertel J, Gretschel S, Schlag PM, Kemmner W, Höcker M. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol. 2006. 24:228–240.
Article
19. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med. 1991. 324:1–8.
20. Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell. 2005. 7:121–127.
Article
21. Achen MG, Mann GB, Stacker SA. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer. 2006. 94:1355–1360.
Article
22. Yonemura Y, Endo Y, Tabata K, Kawamura T, Yun HY, Bandou E, Sasaki T, Miura M. Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer. Int J Clin Oncol. 2005. 10:318–327.
Article
23. Ishikawa M, Kitayama J, Kazama S, Nagawa H. Expression of vascular endothelial growth factor C and D (VEGF-C and -D) is an important risk factor for lymphatic metastasis in undifferentiated early gastric carcinoma. Jpn J Clin Oncol. 2003. 33:21–27.
Article
24. Shida A, Fujioka S, Ishibashi Y, Kobayashi K, Nimura H, Mitsumori N, Suzuki Y, Kawakami M, Urashima M, Yanaga K. Prognostic significance of vascular endothelial growth factor D in gastric carcinoma. World J Surg. 2005. 29:1600–1607.
Article
25. Shida A, Fujioka S, Kobayashi K, Ishibashi Y, Nimura H, Mitsumori N, Yanaga K. Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma. Int J Clin Oncol. 2006. 11:38–43.
Article
26. Kitadai Y, Kodama M, Cho S, Kuroda T, Ochiumi T, Kimura S, Tanaka S, Matsumura S, Yasui W, Chayama K. Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Int J Cancer. 2005. 115:388–392.
Article
27. Onogawa S, Kitadai Y, Amioka T, Kodama M, Cho S, Kuroda T, Ochiumi T, Kimura S, Kuwai T, Tanaka S, Chayama K. 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.
Article
28. Yonemura Y, Fushida S, Bando E, Kinoshita K, Miwa K, Endo Y, Sugiyama K, Partanen T, Yamamoto H, Sasaki T. Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur J Cancer. 2001. 37:918–923.
Article
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