Studying The Relationship Between VEGF-C/VEGFR-3 Expression And Lymphatic Metastasis Of Gastric Cancer

Background: The spread of tumor cells to regional lymph nodes is an early event of gastric cancer metastasis and the status of lymph node metastasis (LNM) is a capital prognostic risk factor for the patients with gastric cancer. At present, the lymphadenectomy is still a main therapeutic method and can not prevent the metastasis of gastric cancer to lymph nodes. Recently, with the development of molecular immunology, molecular biology, molecular pathology and genomelogy, it has an important role and potential therapeutic value to clarify the mechanisms by which gastric carcinoma ceils metastasize to lymph nodes. To date, the mechanisms by which carcinoma cells metastasize to lymph nodes remain unclear. Recently, some studies revealed that vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3) correlated with the growth and regulation of lymphatic vessel, so it is very significant for altering therapeutic regimen for gastric cancer to investigate whether endogenous lymphangiogenic growth factors of tumor can induce lymphatic formation (lymphangiogenesis) and the action of neolymphatic vasculature on lymph node metastasis of cancer. The expression of VEGF-C was most prominently detected in human heart, placenta, muscle, ovary and small intestine and was even higher in several types of human malignant tumors including breast, lung, prostate and colorectal carcinomas. In gastric cancers, it had also been reported that expression of VEGF-C was well correlated with lymphatic invasion and promoted human gastric carcinoma LNM. Therefore, it is of significance to investigate the relationship between expressions of VEGF-C and VEGFR-3 and, LNM and to evaluate the inhibition to the growth of gastric carcinoma cell.Objectives: The present studies aimed at studying the relationship between VEGF-C, VEGFR-3 expression and lymphatic invasion, LNM and to clarify their prognostic significance in gastric carcinoma.Methods Gastric cancer specimens were selected from gastric cancer database from April, 1994 to December, 2000, which were registered and followed up. They were divided into two groups according to LNM existing or not, there was not statistically significant between them in sex, age, tumor location, Borrmann types, histologic categories, depth of infiltrating, serosa invasion, radical gastrectomy extension, peritoneal dissemination and distant organ metastasis. Immunohistochemistry staining was performed with anti-VEGF-C, anti-VEGFR-3, and anti-CD34 monoclonal antibody by DAB method. Their effects on prognosis of gastric cancer patiens were analyzed by Kaplan-meier, Logistc.Results: In 188 cases of gastric cancer, there were 91 patients without LNM, others presented LNM. The positive expression rate(PER) of VEGF-C was 55.23%(104/188) in all specimens, 35.16% ( 32/91 )in group without LNM, 74.23%(72/97)in others(p =0.001). The PER of VEGFR-3 was 34.04% (64/188.) in all cases, 21.98% (20/91) in group without LNM, 45.36% (44/97) in others(p =0.001). The LNM rate was 69.2% (72/104) in group with positive VEGF-C expression, 29.76% (25/84) in negative VEGF-C expression group(p =0.001). The LNM rate was 67.18% (43/64) in group with positive VEGFR-3 expression, 43.55% ( 54/124 ) in negative VEGF-C expression group(p =0.001 ). The CD₃₄ staining was employed to take count of the microvessel density (MVD). There was on statistic significance according to MVD difference between with and without LNM groups. The average lymphatic vessel density(LVD) based on VEGFR-3 staining was 18.48±7.9 in cases without LNM, 26.29±8.5 in patients with LNM(t =-2.437,P=0.016). MVD difference showed on statistic significance between positive and negative VEGF-C expression groups, while LVD did(18.13±10.01 VS. 26.04±13.38, t =-2.459, P=0.015). Five years sum survival was 36% and 59% in group of positive and negative VEGF-C expression respectively (Long rank test p =0.004), 42% and 50% in cases of positive and negative VEGFR-3 expression respectively (Long rank test p =0.042). Conclusions.. The expression of VEGF-C/VEGFR-3 in gastric cancer tissue not only has relationship with LVD and LNM, but also is an important factor which impacts prognosis of gastric cancer patients.