Originally published as JCO Early Release 10.1200/JCO.2004.00.3467 on December 12 2005

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Vascular Endothelial Growth Factor-D and Its Receptor VEGFR-3: Two Novel Independent Prognostic Markers in Gastric Adenocarcinoma

From the Laboratory for Angiogenesis and Tumor Metastasis, Charité, Campus Virchow-Klinikum; Centrum für Anatomie, Institut für Integrative Neuroanatomie, Charité, Campus Mitte; Klinik für Chirurgie und Chirurgische Onkologie, Robert-Rössle-Klinik, Charité, Campus Buch; Max-Delbrück-Zentrum für Molekulare Medizin, Berlin; Institut für Pathologie, Otto-von-Guericke-Universität, Magdeburg, Germany

Address reprint requests to Michael Höcker, MD, Charité, Universitätsmedizin—Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin; e-mail: hoecker{at}charite.de

PURPOSE: Vascular endothelial growth factor (VEGF)-D and its homolog VEGF-C influence lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3), and have been implicated in lymphatic tumor spread. Nodal dissemination of gastric adenocarcinomas critically determines clinical outcome and therapeutic options of affected patients. Therefore, we analyzed expression and prognostic significance of VEGF-D along with VEGF-C, and VEGFR-3 in gastric adenocarcinomas.

MATERIALS AND METHODS: VEGF-C, VEGF-D, and VEGFR-3 were analyzed in 91 R₀-resected primary gastric adenocarcinomas, corresponding noncancerous gastric mucosa, and lymph node metastases employing immunohistochemistry and/or in situ hybridization. Blood and lymph vessel densities were assessed after staining with CD31 and LYVE-1–specific antibodies.

RESULTS: VEGF-D and VEGF-C were detected in 67.0% and 50.5% of gastric cancers, respectively. Healthy gastric mucosa was negative for VEGF-C and in 12.5% positive for VEGF-D. Presence of VEGF-D (P = .005) or VEGF-C (P = .006) was correlated with lymphatic metastases and decreased survival (VEGF-D, P < .05; VEGF-C, P < .05). VEGFR-3 was correlated with reduced carcinoma-specific survival (P < .05), and Cox multivariate regression analysis qualified VEGF-D and VEGFR-3, but not VEGF-C, as independent prognostic parameters. In lymph node–positive gastric cancers, presence of VEGF-D/VEGFR-3 was associated with poor survival, whereas absence of VEGF-D/VEGFR-3 defined a subgroup of patients with clearly favorable prognosis.

CONCLUSION: VEGF-D and VEGFR-3 are novel independent prognostic marker molecules aiding to identify patients with poor prognosis after curative resection of gastric adenocarcinomas. Combined analysis of the VEGF-C/VEGF-D/VEGFR-3 system can be useful to identify patients with unfavorable clinical outcome and thereby may help to refine therapeutic decisions in gastric cancer.

Supported by Grant No. NBLIII TP 3.2 from the Bundesministerium für Bildung und Forschung and by a grant from the Sonnenfeld Stiftung, Berlin, Germany.

S.J. and C.W. contributed equally to this manuscript.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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