Can VEGF-D and VEGFR-3 be used as biomarkers for therapeutic decisions in patients with gastric cancer?

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Detection of lymphatic tumor spread in patients with gastric cancer is important to optimize treatment and assess patient prognosis. VEGF-D and VEGF-C affect lymphangiogenesis via activation of the VEGF receptor 3 (VEGFR-3) and have been implicated in lymphatic spread of gastric adenocarcinoma.


To measure levels of VEGF-D, VEGF-C and VEGFR-3 in gastric adenocarcinomas and correlate the findings with patient survival and clinicopathologic features.


Tissues were obtained from 88 patients who underwent curative gastrectomy between 1995 and 2003 at a single institution. Gastric adenocarcinoma was diagnosed and staged using the WHO classification and the TNM classification of the International Union against Cancer (UICC). Cell culture and quantitative mRNA determination, immunohistochemistry and in situ hybridization were performed. Correlations between positivity for one or more of VEGF-C, VEGF-D and VEGFR-3 and clinicopathologic parameters were evaluated first by univariate analysis, and those parameters found to be significant were then evaluated using the Cox proportional hazards model.


Independent factors affecting tumor-specific and disease-free survival were determined.


Healthy gastric mucosa showed staining for VEGF-D and VEGFR-3 in 12.5% and 83.3% of cases respectively, but VEGF-C was not detected. Gastric adenocarcinomas had increased staining for VEGF-C (50.5%; P<0.001) or VEGF-D (67%; P<0.001). Lymph node metastasis was significantly correlated with immunoreactivity of tumors for VEGF-C (P = 0.006) and VEGF-D (P = 0.005). When staining results were correlated with patient survival according to the Kaplan-Meier algorithm, the presence of VEGF-C or VEGF-D staining was significantly correlated with decreased disease-free survival (P<0.05 in both cases). VEGF-D positivity was also significantly correlated with shorter carcinoma-specific survival (P<0.05). VEGF-C also tended to be associated with shorter carcinoma-specific survival but this was not significant (P = 0.114). Patients who had gastric cancers positive for both VEGF-C and VEGF-D had shorter carcinoma-specific and disease-free survival times (P<0.01 in both cases). On Cox multivariate regression analysis, VEGF-D was an independent prognostic factor for both shorter carcinoma-specific survival (P = 0.017) and shorter disease-free survival (P = 0.023). Similarly, VEGFR-3 was an independent prognostic factor for shorter carcinoma-specific (P = 0.016) and disease-free survival (P = 0.033), but VEGF-C did not qualify as an independent prognostic factor. Among cases with lymph-node metastases, the presence of VEGF-D defined a subset of patients with poor survival, whereas the absence of VEGFR-3 and VEGF-D defined a subgroup of patients who has a 5-year survival of 100%.


Following curative resection of gastric adenocarcinomas, VEGF-D and VEGFR-3 were independent prognostic markers and the VEGF-C/VEGF-D/VEGFR-3 system could be a useful decision-making tool for oncologists.

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