Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms.

Abstract

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.

• Authors: Michiyo Kodama, Yasuhiko Kitadai, Miwako Tanaka, Toshio Kuwai, Shinji Tanaka, Naohide Oue, Wataru Yasui, Kazuaki Chayama
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 22 Pg. 7205-14 (Nov 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19010837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Vascular Endothelial Growth Factor C
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Autocrine Communication (physiology)
• Blotting, Western
• Cell Line, Tumor
• Disease Progression
• Enzyme-Linked Immunosorbent Assay
• Fluorescent Antibody Technique
• Humans
• Immunohistochemistry
• Lymphangiogenesis (physiology)
• Male
• Mice
• Mice, Nude
• Oligonucleotide Array Sequence Analysis
• Paracrine Communication (physiology)
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms (genetics, metabolism, pathology)
• Transfection
• Vascular Endothelial Growth Factor C (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (genetics, metabolism)