Potential role for vascular endothelial growth factor-D as an autocrine factor for human gastric carcinoma cells.
Vascular endothelial growth factor (VEGF)-D induces lymphangiogenesis by activating VEGF receptor (VEGFR)-3, which is expressed mainly by lymphatic endothelial cells. VEGFR-3 has also been detected in several types of malignant cells, but the significance of VEGFR-3 expression by malignant cells remains unclear. We examined the expression and function of VEGF-D/VEGFR-3 in human gastric carcinoma cells. Expression of VEGF-D and VEGFR-3 was analyzed in three human gastric carcinoma cell lines and 29 surgical specimens. cDNA microarray analysis was used to examine the effect of VEGF-D on the expression of genes associated with disease progression in VEGFR-3-expressing KKLS cells. VEGF-D-transfected cells and control cells were transplanted into the gastric wall of nude mice. In 10 of the 29 (34%) gastric carcinoma specimens and two of the three cell lines, cancer cells expressed both VEGF-D and VEGFR-3. In vitro treatment of KKLS cells with exogenous VEGF-D increased expression of cyclin D1 and Bcl-2 and stimulated cell proliferation. VEGF-D transfection into KKLS cells resulted in stimulation of angiogenesis, lymphangiogenesis, and cell proliferation, and in inhibition of apoptosis. VEGF-D may participate in the progression of human gastric carcinoma by acting via autocrine and paracrine mechanisms.
Tanaka
Miwako
M
Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Kitadai
Yasuhiko
Y
Kodama
Michiyo
M
Shinagawa
Kei
K
Sumida
Tomonori
T
Tanaka
Shinji
S
Oue
Naohide
N
Yasui
Wataru
W
Chayama
Kazuaki
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000473:pathology*; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000032:analysis / Q000235:genetics
D019394:Ki-67 Antigen; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3