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Vascular Endothelial Growth Factor C Stimulates Progression of Human Gastric Cancer via Both Autocrine and Paracrine Mechanisms

Authors' Affiliations: Departments of ¹ Medicine and Molecular Science and ² Pathology, Graduate School of Biomedical Sciences, Hiroshima University; ³ Department of Internal Medicine, National Hospital Organization Kure Medical Center; and ⁴ Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan

Requests for reprints: Yasuhiko Kitadai, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Phone: 81-82-257-5193; Fax: 81-82-257-5194; E-mail: kitadai{at}hiroshima-u.ac.jp.

Purpose: Vascular endothelial growth factor (VEGF)-C induces lymphangiogenesis by activating the VEGF receptor (VEGFR)-3, which is expressed by lymphatic endothelial cells. VEGFR-3 has also been detected on several malignant cells, but the significance of VEGFR-3 expression on malignant cells remains unclear. In this study, we examined the expression and function of VEGFR-3 in gastric carcinoma cells.

Experimental Design: We examined the expression of VEGFR-3 by four human gastric carcinoma cell lines and in 36 surgical specimens of gastric carcinoma. We also used cDNA microarrays to examine the effect of VEGF-C on gene expression in VEGFR-3-expressing KKLS cells. To stimulate VEGF-C/VEGFR-3 signaling in an autocrine manner, the VEGF-C expression vector was transfected into KKLS cells, and stable transfectants were established. These cells were then transplanted into the gastric walls of nude mice.

Results: Two of the four gastric carcinoma cell lines expressed VEGFR-3 mRNA. In 17 of 36 gastric carcinoma specimens, VEGFR-3-specific immunoreactivity was detected on tumor cells. In vitro treatment of KKLS cells with VEGF-C stimulated cell proliferation and increased expression of mRNAs encoding cyclin D1, placental growth factor, and autocrine motility factor. Following inoculation of VEGF-C-transfected and control cells into the gastric walls of nude mice, tumor growth of the VEGF-C-transfected cells was greatly accelerated in comparison with that of control cells. Greater angiogenesis and lymphangiogenesis were also detected in VEGF-C-transfected tumors than in control tumors.

Conclusions: Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms.